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Tok K, Gürsoy D, Moulahoum H, Aksu D, Memmedov R, Ghorbanizamani F, Akcam TI, Timur S, Zihnioglu F, Turhan K. Distinct temporal profiles of AMPs and cytokines in pleural fluids from open and closed thoracic surgeries and exploration of synergy with antibiotics and wound healing effects. Microb Pathog 2025; 204:107626. [PMID: 40268151 DOI: 10.1016/j.micpath.2025.107626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 04/17/2025] [Accepted: 04/21/2025] [Indexed: 04/25/2025]
Abstract
Antimicrobial peptides (AMPs) play a crucial role in immune defense and wound healing. Their expression and function in pleural fluids following different thoracic surgeries remain underexplored. This study aims to compare AMP and cytokine profiles in pleural fluids from patients undergoing open and closed thoracic surgeries and assess their antimicrobial efficacy and wound healing potential. Pleural fluid and blood samples were collected from 24 patients at multiple time points post-surgery. Levels of four AMPs (DEF-1β, Angiogenin, RNase7, LL-37) and five cytokines (IL-1β, IL-2, IL-6, IL-8, TNF-α) were measured. Antimicrobial activity against E. coli and S. aureus was tested, including combinations with cefazolin. Wound healing was assessed using an in vitro scratch assay. DEF-1β was significantly higher in open surgeries, while Angiogenin was elevated in closed surgeries. Pleural fluids exhibited strong antimicrobial activity, enhanced when combined with cefazolin. Wound healing was rapid but transient with open surgery fluids and more sustained with closed surgery fluids. The distinct AMP profiles and synergistic effects with antibiotics suggest that pleural fluid-derived AMPs could enhance postoperative care. Further studies are needed to explore their therapeutic potential.
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Affiliation(s)
- Kerem Tok
- Biochemistry Department, Faculty of Science, Ege University, 35100, Bornova, Izmir, Türkiye
| | - Dilara Gürsoy
- Department of Thoracic Surgery, Faculty of Medicine, Ege University, 35100, Bornova, Izmir, Türkiye
| | - Hichem Moulahoum
- Biochemistry Department, Faculty of Science, Ege University, 35100, Bornova, Izmir, Türkiye.
| | - Didem Aksu
- Central Research Testing and Analysis Laboratory Research and Application Center, Ege University, 35100, Bornova, Izmir, Türkiye
| | - Rza Memmedov
- Department of Thoracic Surgery, Faculty of Medicine, Ege University, 35100, Bornova, Izmir, Türkiye
| | - Faezeh Ghorbanizamani
- Biochemistry Department, Faculty of Science, Ege University, 35100, Bornova, Izmir, Türkiye
| | - Tevfik Ilker Akcam
- Department of Thoracic Surgery, Faculty of Medicine, Ege University, 35100, Bornova, Izmir, Türkiye.
| | - Suna Timur
- Biochemistry Department, Faculty of Science, Ege University, 35100, Bornova, Izmir, Türkiye; Central Research Testing and Analysis Laboratory Research and Application Center, Ege University, 35100, Bornova, Izmir, Türkiye
| | - Figen Zihnioglu
- Biochemistry Department, Faculty of Science, Ege University, 35100, Bornova, Izmir, Türkiye
| | - Kutsal Turhan
- Department of Thoracic Surgery, Faculty of Medicine, Ege University, 35100, Bornova, Izmir, Türkiye
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Li X, Dong S, Pan Q, Liu N, Zhang Y. Antibiotic conjugates: Using molecular Trojan Horses to overcome drug resistance. Biomed Pharmacother 2025; 186:118007. [PMID: 40268370 DOI: 10.1016/j.biopha.2025.118007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 10/30/2024] [Accepted: 11/07/2024] [Indexed: 04/25/2025] Open
Abstract
Antimicrobial resistance (AMR) has become a global health crisis due to the rapid emergence of multi-drug-resistant bacteria. The paucity of novel antibiotics in the clinical pipeline has exacerbated this issue, thereby warranting the development of new antibacterial therapies. The 'Trojan Horse' strategy entails conjugating antibiotics with bioactive components that not only facilitate the entry of antibiotic molecules into bacterial cells by circumventing the membrane barriers, but also augment the effects of conventional antibiotics against recalcitrant pathogens. These Trojan Horse elements can also serve as a promising tool for repurposing drugs with hitherto unexamined antimicrobial activity, or drugs with limited clinical utility due to considerable toxic side effects. In this review, we have discussed the current state of research on antibiotic conjugates with monoclonal antibodies (mAbs), antimicrobial peptides (AMPs) and the iron-chelating siderophores. The rationale and mechanisms of different antibiotic conjugates have been summarized, and the preclinical and clinical evidence pertaining to the activity of these conjugates against drug-resistant pathogens have been reviewed. Furthermore, the challenges associated with the clinical translation of these novel antimicrobials, and the future research directions have also been discussed. While antibiotic conjugates offer an attractive alternative to conventional antimicrobials, there are several obstacles to their clinical translation. A greater understanding of the mechanisms underlying AMR, and continuing advances in genetic engineering, synthetic biology, and bioinformatics will be crucial in designing more selective, potent, and safe antibiotic conjugates for tackling multi-drug resistant (MDR) infections.
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Affiliation(s)
- Xi Li
- Department of Vascular and Thyroid Surgery, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Siyuan Dong
- Department of Thoracic surgery, The First Hospital of China Medical University, Shenyang, China
| | - Qi Pan
- Department of Organ Transplantation and Hepatobiliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China; The Key Laboratory of Organ Transplantation in Liaoning Province, Shenyang, Liaoning, China
| | - Ning Liu
- Department of Rehabilitation, the First Affiliated Hospital of China Medical University, Shenyang 110001, China.
| | - Yijie Zhang
- Department of Organ Transplantation and Hepatobiliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China; The Key Laboratory of Organ Transplantation in Liaoning Province, Shenyang, Liaoning, China.
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Baindara P, Kumari S, Dinata R, Mandal SM. Antimicrobial peptides: evolving soldiers in the battle against drug-resistant superbugs. Mol Biol Rep 2025; 52:432. [PMID: 40293554 DOI: 10.1007/s11033-025-10533-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 04/22/2025] [Indexed: 04/30/2025]
Abstract
The discovery of antibiotics was one of the greatest achievements in human history, however, antibiotic resistance evolved no later than the introduction of antibiotics. The rapid evolution of antibiotic-resistant pathogens soon became frightening and remained a global healthcare threat. There is an urgent need to have new alternatives or new strategies to combat the multi-drug resistant superbugs such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Pseudomonas aeruginosa (CR-PA), extended-spectrum β-lactamases (ESBL) bearing multidrug-resistant Acinetobacter baumannii (MDR-AB), Escherichia coli (E. coli), and Klebsiella pneumoniae (K. pneumoniae). Antimicrobial peptides (AMPs) have been considered promising agents equipped with unique mechanisms of action along with several other benefits to fight the battle against drug-resistant superbugs. Overall, the current review summarizes the mechanisms of drug-resistant development, the mechanism of action adopted by AMPs to combat drug-resistant pathogens, and the immunomodulatory properties of AMPs. Additionally, we have also reviewed the synergistic potential of AMPs with conventional antibiotics along with the associated challenges and limitations of AMPs in the way of pharmacological development for therapeutic applications in clinical settings.
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Affiliation(s)
- Piyush Baindara
- Animal Science Research Center, Division of Animal Sciences, University of Missouri, Columbia, MO, 65211, USA.
| | - Sumeeta Kumari
- Department of Oral Biology, School of Dental Medicine, University of Buffalo, Buffalo, NY, 14214, USA
| | - Roy Dinata
- Animal Science Research Center, Division of Animal Sciences, University of Missouri, Columbia, MO, 65211, USA
| | - Santi M Mandal
- Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA
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Kharga K, Jha S, Vishwakarma T, Kumar L. Current developments and prospects of the antibiotic delivery systems. Crit Rev Microbiol 2025; 51:44-83. [PMID: 38425122 DOI: 10.1080/1040841x.2024.2321480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 02/11/2024] [Accepted: 02/16/2024] [Indexed: 03/02/2024]
Abstract
Antibiotics have remained the cornerstone for the treatment of bacterial infections ever since their discovery in the twentieth century. The uproar over antibiotic resistance among bacteria arising from genome plasticity and biofilm development has rendered current antibiotic therapies ineffective, urging the development of innovative therapeutic approaches. The development of antibiotic resistance among bacteria has further heightened the clinical failure of antibiotic therapy, which is often linked to its low bioavailability, side effects, and poor penetration and accumulation at the site of infection. In this review, we highlight the potential use of siderophores, antibodies, cell-penetrating peptides, antimicrobial peptides, bacteriophages, and nanoparticles to smuggle antibiotics across impermeable biological membranes to achieve therapeutically relevant concentrations of antibiotics and combat antimicrobial resistance (AMR). We will discuss the general mechanisms via which each delivery system functions and how it can be tailored to deliver antibiotics against the paradigm of mechanisms underlying antibiotic resistance.
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Affiliation(s)
- Kusum Kharga
- School of Biotechnology, Faculty of Applied Sciences and Biotechnology, Shoolini University, Himachal Pradesh, India
| | - Shubhang Jha
- School of Bioengineering and Food Technology, Faculty of Applied Sciences and Biotechnology, Shoolini University, Himachal Pradesh, India
| | - Tanvi Vishwakarma
- School of Bioengineering and Food Technology, Faculty of Applied Sciences and Biotechnology, Shoolini University, Himachal Pradesh, India
| | - Lokender Kumar
- School of Biotechnology, Faculty of Applied Sciences and Biotechnology, Shoolini University, Himachal Pradesh, India
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Chetty K, Peters XQ, Omolo CA, Ismail EA, Gafar MA, Elhassan E, Kassam SZF, Govender J, Dlamini S, Govender T. Multifunctional Dual Enzyme-Responsive Nanostructured Lipid Carriers for Targeting and Enhancing the Treatment of Bacterial Infections. ACS APPLIED BIO MATERIALS 2025; 8:548-569. [PMID: 39714140 DOI: 10.1021/acsabm.4c01436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Bacterial infections pose an increasingly worrisome threat to the health of humankind, with antibiotic resistance contributing significantly to this burden. With current conventional antibiotics perpetuating the problem, and a paucity in developing antibiotics, drug delivery systems incorporating nanotechnology appear promising. As such, a dual enzyme-responsive multifunctional nanostructured lipid carrier (NLC) incorporating farnesol (FAN) and triglycerol monostearate (TGMS), was conceptualized for the codelivery of vancomycin (VCM) and antimicrobial peptide (AMP) to enhance the antibacterial activity of VCM. In silico studies and Microscale Thermophoresis demonstrated the strong binding relationships between the NLC constituents and two enzymes that exist in higher concentrations during host infection, namely lipase and a matrix metalloproteinase (MMP). The formulated nanosystem, VCM-AMP-TF-NLCs, had a particle size, polydispersity index, zeta potential, and entrapment efficiency of 149.00 ± 2.97 nm, 0.07 ± 0.01, -5.51 ± 1.21 mV, and 86.20% ± 1.47%, respectively. The NLCs, which showed stability, and biocompatibility, also demonstrated lipase- and MMP-responsiveness. The in vitro antibacterial studies revealed 2-fold and 8-fold reductions in the minimum inhibitory concentration for the NLCs compared to bare VCM, against methicillin-resistant Staphylococcal aureus (MRSA) and Escherichia coli, respectively. Furthermore, in vivo studies revealed that tissues treated with the VCM-AMP-TF-NLCs displayed significantly reduced bacterial burdens (up to 8.73-fold) and less histopathological cellular injury, edema, and necrosis compared to the tissues treated with bare VCM alone. The results support the superiority of the VCM-AMP-TF-NLCs as a multifunctional dual enzyme-responsive NLC compared to bare VCM.
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Affiliation(s)
- Kerisha Chetty
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
| | - Xylia Q Peters
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
| | - Calvin A Omolo
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
- Department of Pharmaceutics, School of Pharmacy and Health Sciences, United States International University-Africa, P.O. Box 14634, Nairobi 00800, Kenya
| | - Eman A Ismail
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
| | - Mohammed A Gafar
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
| | - Eman Elhassan
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
| | - Sania Z F Kassam
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
| | - Jasoda Govender
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
| | - Sbongumusa Dlamini
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
| | - Thirumala Govender
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4300, South Africa
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Ghanbarzadeh Z, Mohagheghzadeh A, Hemmati S. The Roadmap of Plant Antimicrobial Peptides Under Environmental Stress: From Farm to Bedside. Probiotics Antimicrob Proteins 2024; 16:2269-2304. [PMID: 39225894 DOI: 10.1007/s12602-024-10354-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
Antimicrobial peptides (AMPs) are the most favorable alternatives in overcoming multidrug resistance, alone or synergistically with conventional antibiotics. Plant-derived AMPs, as cysteine-rich peptides, widely compensate the pharmacokinetic drawbacks of peptide therapeutics. Compared to the putative genes encrypted in the genome, AMPs that are produced under stress are active forms with the ability to combat resistant microbial species. Within this study, plant-derived AMPs, namely, defensins, nodule-specific cysteine-rich peptides, snakins, lipid transfer proteins, hevein-like proteins, α-hairpinins, and aracins, expressed under biotic and abiotic stresses, are classified. We could observe that while α-hairpinins and snakins display a helix-turn-helix structure, conserved motif patterns such as β1αβ2β3 and β1β2β3 exist in plant defensins and hevein-like proteins, respectively. According to the co-expression data, several plant AMPs are expressed together to trigger synergistic effects with membrane disruption mechanisms such as toroidal pore, barrel-stave, and carpet models. The application of AMPs as an eco-friendly strategy in maintaining agricultural productivity through the development of transgenes and bio-pesticides is discussed. These AMPs can be consumed in packaging material, wound-dressing products, coating catheters, implants, and allergology. AMPs with cell-penetrating properties are verified for the clearance of intracellular pathogens. Finally, the dominant pharmacological activities of bioactive peptides derived from the gastrointestinal digestion of plant AMPs, namely, inhibitors of renin and angiotensin-converting enzymes, dipeptidyl peptidase IV and α-glucosidase inhibitors, antioxidants, anti-inflammatory, immunomodulating, and hypolipidemic peptides, are analyzed. Conclusively, as phytopathogens and human pathogens can be affected by plant-derived AMPs, they provide a bright perspective in agriculture, breeding, food, cosmetics, and pharmaceutical industries, translated as farm to bedside.
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Affiliation(s)
- Zohreh Ghanbarzadeh
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolali Mohagheghzadeh
- Department of Phytopharmaceuticals, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shiva Hemmati
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
- Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, UCSI University, Cheras, 56000, Kuala Lumpur, Malaysia.
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Jeyarajan S, Peter AS, Ranjith S, Sathyan A, Duraisamy S, Kandasamy I, Chidambaram P, Kumarasamy A. Glycine-replaced epinecidin-1 variant bestows better stability and stronger antimicrobial activity against a range of nosocomial pathogenic bacteria. Biotechnol Appl Biochem 2024; 71:1384-1404. [PMID: 39034467 DOI: 10.1002/bab.2637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 06/29/2024] [Indexed: 07/23/2024]
Abstract
Epinecidin-1 (epi-1), an antimicrobial peptide first identified in marine grouper fish, has multifunctional bioactivities. The present study aims to improve its therapeutic potential via structural modifications that could enhance its antimicrobial activity and stability. To achieve it, we replaced glycine and the first histidine in the parent epi-1 with lysine, which resulted in a peptide with a repeating KXXK motif and improved physiochemical properties related to antimicrobial activity. This modified peptide, referred to as glycine-to-lysine replaced-epi-1, also gained stability and a twofold increase in helical propensity. To produce the active peptide, overlap extension PCR was employed to generate the gene of GK-epi-1 via site-directed mutagenesis, which was then cloned into the pET-32a vector and expressed as a recombinant fusion protein in Escherichia coli C43 (DE3) strain. The recombinant protein was purified and digested with enterokinase to release the active peptide fragment, which was then evaluated for antimicrobial activity and stability. The lysine substitution led to an enhancement in broad-spectrum antimicrobial activity against a wide range of nosocomial pathogenic bacteria.
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Affiliation(s)
- Sivakumar Jeyarajan
- Microbial Biotechnology Laboratory, Department of Marine Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
- Transgeinc Animal Model Core, Biomedical Research Core Facilities, University of Michigan, Ann Arbor, Michigan, USA
| | - Ansu Susan Peter
- Microbial Biotechnology Laboratory, Department of Marine Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Sukumar Ranjith
- Microbial Biotechnology Laboratory, Department of Marine Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Aswathy Sathyan
- Microbial Biotechnology Laboratory, Department of Marine Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Senbagam Duraisamy
- Microbial Biotechnology Laboratory, Department of Marine Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
- Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Indira Kandasamy
- Microbial Biotechnology Laboratory, Department of Marine Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | | | - Anbarasu Kumarasamy
- Microbial Biotechnology Laboratory, Department of Marine Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
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Sedaghati M, Akbari R, Lotfollahi Hagghi L, Yousefi S, Mesbahi T, Delfi M. Survey of probable synergism between melittin and ciprofloxacin, rifampicin, and chloramphenicol against multidrug-resistant Pseudomonas aeruginosa. Front Microbiol 2024; 15:1480299. [PMID: 39640853 PMCID: PMC11617520 DOI: 10.3389/fmicb.2024.1480299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024] Open
Abstract
Background The emergence of multidrug-resistant bacteria and also biofilm-associated infections is a great health concern due to the failure of available antibiotics. This has alerted scientists to developing alternative antibiotics. Melittin as an antimicrobial peptide has antibacterial synergistic activity in combining with conventional antibiotics against pathogenic bacteria. Accordingly, this study aimed to assess the synergistic effect of melittin in combination with Ciprofloxacin, Rifampicin, and Chloramphenicol against MDR strains of P. aeruginosa. Materials and methods Fifty strains of P. aeruginosa were isolated from clinical specimens. The antibiotic susceptibility of isolates was evaluated by the disk diffusion method. The MIC and MBC of melittin and melittin-antibiotics combination against isolated strains were examined by microdilution method. The probable synergism between melittin and antibiotics was assayed using the FIC protocol. Time-killing kinetics and anti-biofilm effects of melittin and melittin-antibiotics combination were evaluated using time-kill kinetics and crystal violet staining method, respectively. The toxicity of the melittin-antibiotics combination on the HEK293 cell line was also assessed by the MTT assay method. Results Out of 50 isolates of P. aeruginosa, 15 strains are considered to be multidrug strains. Among MDR strains of P. aeruginosa, 42.85% were resistant to cefepime and ceftazidime and all urine-originate isolates were resistant to cotrimoxazole. A combination of MIC dose of ciprofloxacin and melittin decreased resistance against ciprofloxacin up to 33%. The ciprofloxacin-melittin combination showed a favorable synergism and anti-biofilm effect and was also 30.3% less toxic than melittin alone at 4 μg/ml against the HEK293 cell line. In contrast to ciprofloxacin, with the melittin-rifampicin and melittin-chloramphenicol combinations, an addition effect occurred, respectively, in 86.66 and 53.33% of MDR strains of P. aeruginosa. Conclusion Combining melittin's antibacterial and anti-biofilm properties with traditional antibiotics may offer a novel strategy to address antibiotic resistance in P. aeruginosa. The simultaneous administration of melittin and ciprofloxacin in a single dose has shown a marked increase in antibacterial effectiveness while minimizing toxicity to the HEK293 cell line. It is advisable to conduct additional research to explore the combined antibacterial effects of melittin and ciprofloxacin in a wider range of clinical samples, animal models, and clinical trial settings.
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Affiliation(s)
| | - Reza Akbari
- Department of Microbiology and Virology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Lida Lotfollahi Hagghi
- Department of Microbiology and Virology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Sahle Z, Engidaye G, Shenkute Gebreyes D, Adenew B, Abebe TA. Fecal microbiota transplantation and next-generation therapies: A review on targeting dysbiosis in metabolic disorders and beyond. SAGE Open Med 2024; 12:20503121241257486. [PMID: 38826830 PMCID: PMC11143861 DOI: 10.1177/20503121241257486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 05/09/2024] [Indexed: 06/04/2024] Open
Abstract
The human microbiome, particularly the gut microbiome, has emerged as a central determinant of health and disease. Dysbiosis, an imbalance in the microbial composition of the gut, is associated with a variety of metabolic and other diseases, highlighting the potential for microbiota-targeted treatments. Fecal microbiota transplantation has received considerable attention as a promising therapy to modulate the gut microbiome and restore microbial homeostasis. However, challenges remain, including standardization, safety, and long-term efficacy. This review summarizes current knowledge on fecal microbiota transplantation and describes the next generation therapies targeting microbiome. This review looked at the mechanistic understanding of fecal microbiota transplantation and alternative strategies, elucidating their potential role in improving dysbiosis-associated metabolic disorders, such as obesity, and type 2 diabetes and others. Additionally, this review discussed the growing application of therapies targeting the gut microbiome. Insights from clinical trials, preclinical studies, and emerging technologies provide a comprehensive overview of the evolving landscape of microbiome-based interventions. Through a critical assessment of current advances and prospects, this review aims to highlight the therapeutic potential of targeting gut microbiome and pave the way for innovative approaches in precision medicine and personalized treatments.
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Affiliation(s)
- Zenawork Sahle
- Department of Medical Laboratory Science, Asrat Weldeyes Health Science Campus, Debre Berhan University, Debre Berhan, Ethiopia
| | - Getabalew Engidaye
- Department of Medical Laboratory Science, Asrat Weldeyes Health Science Campus, Debre Berhan University, Debre Berhan, Ethiopia
| | - Demissew Shenkute Gebreyes
- Department of Medical Laboratory Science, Asrat Weldeyes Health Science Campus, Debre Berhan University, Debre Berhan, Ethiopia
| | - Behailu Adenew
- Department of Medical Laboratory Science, Debre Berhan Compressive Specialized Hospital, Debre Berhan, Ethiopia
| | - Tsegahun Asfaw Abebe
- Department of Medical Laboratory Science, Asrat Weldeyes Health Science Campus, Debre Berhan University, Debre Berhan, Ethiopia
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Chen C, Shi J, Wang D, Kong P, Wang Z, Liu Y. Antimicrobial peptides as promising antibiotic adjuvants to combat drug-resistant pathogens. Crit Rev Microbiol 2024; 50:267-284. [PMID: 36890767 DOI: 10.1080/1040841x.2023.2186215] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/19/2022] [Accepted: 10/26/2022] [Indexed: 03/10/2023]
Abstract
The widespread antimicrobial resistance (AMR) calls for the development of new antimicrobial strategies. Antibiotic adjuvant rescues antibiotic activity and increases the life span of the antibiotics, representing a more productive, timely, and cost-effective strategy in fighting drug-resistant pathogens. Antimicrobial peptides (AMPs) from synthetic and natural sources are considered new-generation antibacterial agents. Besides their direct antimicrobial activity, growing evidence shows that some AMPs effectively enhance the activity of conventional antibiotics. The combinations of AMPs and antibiotics display an improved therapeutic effect on antibiotic-resistant bacterial infections and minimize the emergence of resistance. In this review, we discuss the value of AMPs in the age of resistance, including modes of action, limiting evolutionary resistance, and their designing strategies. We summarise the recent advances in combining AMPs and antibiotics against antibiotic-resistant pathogens, as well as their synergistic mechanisms. Lastly, we highlight the challenges and opportunities associated with the use of AMPs as potential antibiotic adjuvants. This will shed new light on the deployment of synergistic combinations to address the AMR crisis.
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Affiliation(s)
- Chen Chen
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Jingru Shi
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Dejuan Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Pan Kong
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Zhiqiang Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Yuan Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, China
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11
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Escobar-Salom M, Barceló IM, Rojo-Molinero E, Jordana-Lluch E, Cabot G, Oliver A, Juan C. In vitro activity of human defensins HNP-1 and hBD-3 against multidrug-resistant ESKAPE Gram-negatives of clinical origin and selected peptidoglycan recycling-defective mutants. Microbiol Spectr 2024; 12:e0035824. [PMID: 38441982 PMCID: PMC10986477 DOI: 10.1128/spectrum.00358-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 02/20/2024] [Indexed: 03/07/2024] Open
Abstract
The use of immune compounds as antimicrobial adjuvants is a classic idea recovering timeliness in the current antibiotic resistance scenario. However, the activity of certain antimicrobial peptides against ESKAPE Gram-negatives has not been sufficiently investigated. The objective of this study was to determine the activities of human defensins HNP-1 and hBD-3 alone or combined with permeabilizing/peptidoglycan-targeting agents against clinical ESKAPE Gram-negatives [Acinetobacter baumannii (AB), Enterobacter cloacae (EC), Klebsiella pneumoniae (KP), and acute/chronic Pseudomonas aeruginosa (PA)]. Lethal concentrations (LCs) of HNP-1 and hBD-3 were determined in four collections of multidrug resistant EC, AB, KP, and PA clinical strains (10-36 isolates depending on the collection). These defensins act through membrane permeabilization plus peptidoglycan building blockade, enabling that alterations in peptidoglycan recycling may increase their activity, which is why different recycling-defective mutants were also included. Combinations with physiological lysozyme and subinhibitory colistin for bactericidal activities determination, and with meropenem for minimum inhibitory concentrations (MICs), were also assessed. HNP-1 showed undetectable activity (LC > 32 mg/L for all strains). hBD-3 showed appreciable activities: LC ranges 2-16, 8-8, 8->32, and 8->32 mg/L for AB, EC, KP, and PA, being PA strains from cystic fibrosis significantly more resistant than acute origin ones. None of the peptidoglycan recycling-defective mutants showed greater susceptibility to HNP-1/hBD-3. Combination with colistin or lysozyme did not change their bactericidal power, and virtually neither did meropenem + hBD-3 compared to meropenem MICs. This is the first study comparatively analyzing the HNP-1/hBD-3 activities against the ESKAPE Gram-negatives, and demonstrates interesting bactericidal capacities of hBD-3 mostly against AB and EC. IMPORTANCE In the current scenario of critical need for new antimicrobials against multidrug-resistant bacteria, all options must be considered, including classic ideas such as the use of purified immune compounds. However, information regarding the activity of certain human defensins against ESKAPE Gram-negatives was incomplete. This is the first study comparatively assessing the in vitro activity of two membrane-permeabilizing/peptidoglycan construction-blocking defensins (HNP-1 and hBD-3) against relevant clinical collections of ESKAPE Gram-negatives, alone or in combination with permeabilizers, additional peptidoglycan-targeting attacks, or the blockade of its recycling. Our data suggest that hBD-3 has a notable bactericidal activity against multidrug-resistant Acinetobacter baumannii and Enterobacter cloacae strains that should be considered as potential adjuvant option. Our results suggest for the first time an increased resistance of Pseudomonas aeruginosa strains from chronic infection compared to acute origin ones, and provide new clues about the predominant mode of action of hBD-3 against Gram-negatives (permeabilization rather than peptidoglycan-targeting).
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Affiliation(s)
- María Escobar-Salom
- Research Unit, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Microbiology Department, University Hospital Son Espases, Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
| | - Isabel María Barceló
- Research Unit, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Microbiology Department, University Hospital Son Espases, Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
| | - Estrella Rojo-Molinero
- Research Unit, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Microbiology Department, University Hospital Son Espases, Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
| | - Elena Jordana-Lluch
- Research Unit, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Microbiology Department, University Hospital Son Espases, Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
| | - Gabriel Cabot
- Research Unit, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Microbiology Department, University Hospital Son Espases, Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
| | - Antonio Oliver
- Research Unit, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Microbiology Department, University Hospital Son Espases, Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
| | - Carlos Juan
- Research Unit, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
- Microbiology Department, University Hospital Son Espases, Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
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12
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Tao Q, Lu Y, Liu Q, Chen R, Xu Y, Li G, Hu X, Ye C, Peng L, Fang R. Antibacterial activity of the antimicrobial peptide PMAP-36 in combination with tetracycline against porcine extraintestinal pathogenic Escherichia coli in vitro and in vivo. Vet Res 2024; 55:35. [PMID: 38520031 PMCID: PMC10960472 DOI: 10.1186/s13567-024-01295-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 02/28/2024] [Indexed: 03/25/2024] Open
Abstract
The increase in the emergence of antimicrobial resistance has led to great challenges in controlling porcine extraintestinal pathogenic Escherichia coli (ExPEC) infections. Combinations of antimicrobial peptides (AMPs) and antibiotics can synergistically improve antimicrobial efficacy and reduce bacterial resistance. In this study, we investigated the antibacterial activity of porcine myeloid antimicrobial peptide 36 (PMAP-36) in combination with tetracycline against porcine ExPEC PCN033 both in vitro and in vivo. The minimum bactericidal concentrations (MBCs) of AMPs (PMAP-36 and PR-39) against the ExPEC strains PCN033 and RS218 were 10 μM and 5 μM, respectively. Results of the checkerboard assay and the time-kill assay showed that PMAP-36 and antibiotics (tetracycline and gentamicin) had synergistic bactericidal effects against PCN033. PMAP-36 and tetracycline in combination led to PCN033 cell wall shrinkage, as was shown by scanning electron microscopy. Furthermore, PMAP-36 delayed the emergence of PCN033 resistance to tetracycline by inhibiting the expression of the tetracycline resistance gene tetB. In a mouse model of systemic infection of PCN033, treatment with PMAP-36 combined with tetracycline significantly increased the survival rate, reduced the bacterial load and dampened the inflammatory response in mice. In addition, detection of immune cells in the peritoneal lavage fluid using flow cytometry revealed that the combination of PMAP-36 and tetracycline promoted the migration of monocytes/macrophages to the infection site. Our results suggest that AMPs in combination with antibiotics may provide more therapeutic options against multidrug-resistant porcine ExPEC.
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Affiliation(s)
- Qi Tao
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China
| | - Yi Lu
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China
| | - Qian Liu
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China
| | - Runqiu Chen
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China
| | - Yating Xu
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China
| | - Gang Li
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China
| | - Xiaoxiang Hu
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China
| | - Chao Ye
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China
| | - Lianci Peng
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China.
| | - Rendong Fang
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, 400715, China.
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13
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Di Napoli M, Castagliuolo G, Pio S, Di Nardo I, Russo T, Antonini D, Notomista E, Varcamonti M, Zanfardino A. Study of the Antimicrobial Activity of the Human Peptide SQQ30 against Pathogenic Bacteria. Antibiotics (Basel) 2024; 13:145. [PMID: 38391531 PMCID: PMC10886087 DOI: 10.3390/antibiotics13020145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/19/2024] [Accepted: 01/30/2024] [Indexed: 02/24/2024] Open
Abstract
Given the continuous increase in antibiotic resistance, research has been driven towards the isolation of new antimicrobial molecules. Short, charged, and very hydrophobic antimicrobial peptides have a direct action against biological membranes, which are less prone to developing resistance. Using a bioinformatic tool, we chose the SQQ30 peptide, isolated from the human SOGA1 protein. The antimicrobial activity of this peptide against various Gram-negative and Gram-positive bacterial strains and against a fungal strain was studied. A mechanism of action directed against biological membranes was outlined. When administered in combination with the antibiotic ciprofloxacin and with the TRS21 (buforin II), another antimicrobial peptide, SQQ30 can be used with a lower MIC, showing additivity and synergism, respectively. Particularly interesting is the ability of SQQ30 to bind LPS in Gram-negative strains, preventing the eukaryotic cell from releasing inflammatory mediators. Our study indicates SQQ30 as a novel and promising antimicrobial agent.
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Affiliation(s)
- Michela Di Napoli
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Giusy Castagliuolo
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Sara Pio
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Ilaria Di Nardo
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Teresa Russo
- IPCB-Institute for Polymers, Composites and Biomaterials, National Research Council of Italy, 80125 Naples, Italy
| | - Dario Antonini
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Eugenio Notomista
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Mario Varcamonti
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Anna Zanfardino
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
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14
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Oludiran A, Malik A, Zourou AC, Wu Y, Gross SP, Siryapon A, Poudel A, Alleyne K, Adams S, Courson DS, Cotten ML, Purcell EB. Host-defense piscidin peptides as antibiotic adjuvants against Clostridioides difficile. PLoS One 2024; 19:e0295627. [PMID: 38252641 PMCID: PMC10802969 DOI: 10.1371/journal.pone.0295627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 11/26/2023] [Indexed: 01/24/2024] Open
Abstract
The spore-forming intestinal pathogen Clostridioides difficile causes multidrug resistant infection with a high rate of recurrence after treatment. Piscidins 1 (p1) and 3 (p3), cationic host defense peptides with micromolar cytotoxicity against C. difficile, sensitize C. difficile to clinically relevant antibiotics tested at sublethal concentrations. Both peptides bind to Cu2+ using an amino terminal copper and nickel binding motif. Here, we investigate the two peptides in the apo and holo states as antibiotic adjuvants against an epidemic strain of C. difficile. We find that the presence of the peptides leads to lower doses of metronidazole, vancomycin, and fidaxomicin to kill C. difficile. The activity of metronidazole, which targets DNA, is enhanced by a factor of 32 when combined with p3, previously shown to bind and condense DNA. Conversely, the activity of vancomycin, which acts at bacterial cell walls, is enhanced 64-fold when combined with membrane-active p1-Cu2+. As shown through microscopy monitoring the permeabilization of membranes of C. difficile cells and vesicle mimics of their membranes, the adjuvant effect of p1 and p3 in the apo and holo states is consistent with a mechanism of action where the peptides enable greater antibiotic penetration through the cell membrane to increase their bioavailability. The variations in effects obtained with the different forms of the peptides reveal that while all piscidins generally sensitize C. difficile to antibiotics, co-treatments can be optimized in accordance with the underlying mechanism of action of the peptides and antibiotics. Overall, this study highlights the potential of antimicrobial peptides as antibiotic adjuvants to increase the lethality of currently approved antibiotic dosages, reducing the risk of incomplete treatments and ensuing drug resistance.
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Affiliation(s)
- Adenrele Oludiran
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia, United States of America
| | - Areej Malik
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia, United States of America
- Biomedical Sciences Program, Old Dominion University, Norfolk, Virginia, United States of America
| | - Andriana C. Zourou
- Department of Applied Science, William & Mary, Williamsburg, Virginia, United States of America
| | - Yonghan Wu
- Irvine Department of Physics and Astronomy, University of California, Los Angeles, California, United States of America
| | - Steven P. Gross
- Ivrine Department of Developmental and Cell Biology, University of California, Los Angeles, California, United States of America
| | - Albert Siryapon
- Irvine Department of Physics and Astronomy, University of California, Los Angeles, California, United States of America
| | - Asia Poudel
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia, United States of America
| | - Kwincy Alleyne
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia, United States of America
| | - Savion Adams
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia, United States of America
| | - David S. Courson
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia, United States of America
| | - Myriam L. Cotten
- Department of Applied Science, William & Mary, Williamsburg, Virginia, United States of America
| | - Erin B. Purcell
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia, United States of America
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15
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Baindara P, Mandal SM. Gut-Antimicrobial Peptides: Synergistic Co-Evolution with Antibiotics to Combat Multi-Antibiotic Resistance. Antibiotics (Basel) 2023; 12:1732. [PMID: 38136766 PMCID: PMC10740742 DOI: 10.3390/antibiotics12121732] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023] Open
Abstract
Due to huge diversity and dynamic competition, the human gut microbiome produces a diverse array of antimicrobial peptides (AMPs) that play an important role in human health. The gut microbiome has an important role in maintaining gut homeostasis by the AMPs and by interacting with other human organs via established connections such as the gut-lung, and gut-brain axis. Additionally, gut AMPs play a synergistic role with other gut microbiota and antimicrobials to maintain gut homeostasis by fighting against multi-antibiotic resistance (MAR) bacteria. Further, conventional antibiotics intake creates a synergistic evolutionary pressure for gut AMPs, where antibiotics and gut AMPs fight synergistically against MAR. Overall, gut AMPs are evolving under a complex and highly synergistic co-evolutionary pressure created by the various interactions between gut microbiota, gut AMPs, and antibiotics; however, the complete mechanism is not well understood. The current review explores the synergistic action of gut AMPs and antibiotics along with possibilities to fight against MAR bacteria.
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Affiliation(s)
- Piyush Baindara
- Radiation Oncology, NextGen Precision Health, School of Medicine, University of Missouri, Columbia, MO 65211, USA
| | - Santi M. Mandal
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India;
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16
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Mhlongo JT, Waddad AY, Albericio F, de la Torre BG. Antimicrobial Peptide Synergies for Fighting Infectious Diseases. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300472. [PMID: 37407512 PMCID: PMC10502873 DOI: 10.1002/advs.202300472] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/28/2023] [Indexed: 07/07/2023]
Abstract
Antimicrobial peptides (AMPs) are essential elements of thehost defense system. Characterized by heterogenous structures and broad-spectrumaction, they are promising candidates for combating multidrug resistance. Thecombined use of AMPs with other antimicrobial agents provides a new arsenal ofdrugs with synergistic action, thereby overcoming the drawback of monotherapiesduring infections. AMPs kill microbes via pore formation, thus inhibitingintracellular functions. This mechanism of action by AMPs is an advantage overantibiotics as it hinders the development of drug resistance. The synergisticeffect of AMPs will allow the repurposing of conventional antimicrobials andenhance their clinical outcomes, reduce toxicity, and, most significantly,prevent the development of resistance. In this review, various synergies ofAMPs with antimicrobials and miscellaneous agents are discussed. The effect ofstructural diversity and chemical modification on AMP properties is firstaddressed and then different combinations that can lead to synergistic action,whether this combination is between AMPs and antimicrobials, or AMPs andmiscellaneous compounds, are attended. This review can serve as guidance whenredesigning and repurposing the use of AMPs in combination with other antimicrobialagents for enhanced clinical outcomes.
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Affiliation(s)
- Jessica T. Mhlongo
- KwaZulu‐Natal Research Innovation and Sequencing Platform (KRISP)School of Laboratory Medicine and Medical SciencesCollege of Health SciencesUniversity of KwaZulu‐NatalDurban4041South Africa
- Peptide Science LaboratorySchool of Chemistry and PhysicsUniversity of KwaZulu‐NatalWestvilleDurban4000South Africa
| | - Ayman Y. Waddad
- Peptide Science LaboratorySchool of Chemistry and PhysicsUniversity of KwaZulu‐NatalWestvilleDurban4000South Africa
| | - Fernando Albericio
- Peptide Science LaboratorySchool of Chemistry and PhysicsUniversity of KwaZulu‐NatalWestvilleDurban4000South Africa
- CIBER‐BBNNetworking Centre on BioengineeringBiomaterials and Nanomedicineand Department of Organic ChemistryUniversity of BarcelonaBarcelona08028Spain
| | - Beatriz G. de la Torre
- KwaZulu‐Natal Research Innovation and Sequencing Platform (KRISP)School of Laboratory Medicine and Medical SciencesCollege of Health SciencesUniversity of KwaZulu‐NatalDurban4041South Africa
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17
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Ioannou P, Baliou S, Kofteridis DP. Antimicrobial Peptides in Infectious Diseases and Beyond-A Narrative Review. Life (Basel) 2023; 13:1651. [PMID: 37629508 PMCID: PMC10455936 DOI: 10.3390/life13081651] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/27/2023] Open
Abstract
Despite recent medical research and clinical practice developments, the development of antimicrobial resistance (AMR) significantly limits therapeutics for infectious diseases. Thus, novel treatments for infectious diseases, especially in this era of increasing AMR, are urgently needed. There is ongoing research on non-classical therapies for infectious diseases utilizing alternative antimicrobial mechanisms to fight pathogens, such as bacteriophages or antimicrobial peptides (AMPs). AMPs are evolutionarily conserved molecules naturally produced by several organisms, such as plants, insects, marine organisms, and mammals, aiming to protect the host by fighting pathogenic microorganisms. There is ongoing research regarding developing AMPs for clinical use in infectious diseases. Moreover, AMPs have several other non-medical applications in the food industry, such as preservatives, animal husbandry, plant protection, and aquaculture. This review focuses on AMPs, their origins, biology, structure, mechanisms of action, non-medical applications, and clinical applications in infectious diseases.
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Affiliation(s)
- Petros Ioannou
- School of Medicine, University of Crete, 71003 Heraklion, Greece
- Internal Medicine, University Hospital of Heraklion, 71110 Heraklion, Greece
| | - Stella Baliou
- Internal Medicine, University Hospital of Heraklion, 71110 Heraklion, Greece
| | - Diamantis P. Kofteridis
- School of Medicine, University of Crete, 71003 Heraklion, Greece
- Internal Medicine, University Hospital of Heraklion, 71110 Heraklion, Greece
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18
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Liu T, Sun Z, Yang Z, Qiao X. Microbiota-derived short-chain fatty acids and modulation of host-derived peptides formation: Focused on host defense peptides. Biomed Pharmacother 2023; 162:114586. [PMID: 36989711 DOI: 10.1016/j.biopha.2023.114586] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/12/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
The byproducts of bacterial fermentation known as short-chain fatty acids (SCFAs) are chemically comprised of a carboxylic acid component and a short hydrocarbon chain. Recent investigations have demonstrated that SCFAs can affect intestinal immunity by inducing endogenous host defense peptides (HDPs) and their beneficial effects on barrier integrity, gut health, energy supply, and inflammation. HDPs, which include defensins, cathelicidins, and C-type lectins, perform a significant function in innate immunity in gastrointestinal mucosal membranes. SCFAs have been demonstrated to stimulate HDP synthesis by intestinal epithelial cells via interactions with G protein-coupled receptor 43 (GPR43), activation of the Jun N-terminal kinase (JNK) and Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, and the cell growth pathways. Furthermore, SCFA butyrate has been demonstrated to enhance the number of HDPs released from macrophages. SCFAs promote monocyte-to-macrophage development and stimulate HDP synthesis in macrophages by inhibiting histone deacetylase (HDAC). Understanding the etiology of many common disorders might be facilitated by studies into the function of microbial metabolites, such as SCFAs, in the molecular regulatory processes of immune responses (e.g., HDP production). This review will focus on the current knowledge of the role and mechanism of microbiota-derived SCFAs in influencing the synthesis of host-derived peptides, particularly HDPs.
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Synergy between Human Peptide LL-37 and Polymyxin B against Planktonic and Biofilm Cells of Escherichia coli and Pseudomonas aeruginosa. Antibiotics (Basel) 2023; 12:antibiotics12020389. [PMID: 36830299 PMCID: PMC9952724 DOI: 10.3390/antibiotics12020389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 02/01/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
The rise in antimicrobial resistant bacteria is limiting the number of effective treatments for bacterial infections. Escherichia coli and Pseudomonas aeruginosa are two of the pathogens with the highest prevalence of resistance, and with the greatest need for new antimicrobial agents. Combinations of antimicrobial peptides (AMPs) and antibiotics that display synergistic effects have been shown to be an effective strategy in the development of novel therapeutic agents. In this study, we investigated the synergy between the AMP LL-37 and various classes of antibiotics against E. coli and P. aeruginosa strains. Of the six antibiotics tested (ampicillin, tetracycline, ciprofloxacin, gentamicin, aztreonam, and polymyxin B (PMB)), LL-37 displayed the strongest synergy against E. coli MG1655 and P. aeruginosa PAO1 laboratory strains when combined with PMB. Given the strong synergy, the PMB + LL-37 combination was chosen for further examination where it demonstrated synergy against multidrug-resistant and clinical E. coli isolates. Synergy of PMB + LL-37 towards clinical isolates of P. aeruginosa varied and showed synergistic, additive, or indifferent effects. The PMB + LL-37 combination treatment showed significant prevention of biofilm formation as well as eradication of pre-grown E. coli and P. aeruginosa biofilms. Using the Galleria mellonella wax worm model, we showed that the PMB + LL-37 combination treatment retained its antibacterial capacities in vivo. Flow analyses were performed to characterize the mode of action. The results of the present study provide proof of principle for the synergistic response between LL-37 and PMB and give novel insights into a promising new antimicrobial combination against gram-negative planktonic and biofilm cells.
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Structural Basis of Peptide-Based Antimicrobial Inhibition of a Resistance-Nodulation-Cell Division Multidrug Efflux Pump. Microbiol Spectr 2022; 10:e0299022. [PMID: 36121287 PMCID: PMC9603588 DOI: 10.1128/spectrum.02990-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Bacterial efflux pumps in the resistance-nodulation-cell division (RND) family of Gram-negative bacteria contribute significantly to the development of antimicrobial resistance by many pathogens. In this study, we selected the MtrD transporter protein of Neisseria gonorrhoeae as it is the sole RND pump possessed by this strictly human pathogen and can export multiple antimicrobials, including antibiotics, bile salts, detergents, dyes, and antimicrobial peptides. Using knowledge from our previously published structures of MtrD in the presence or absence of bound antibiotics as a model and the known ability of MtrCDE to export cationic antimicrobial peptides, we hypothesized that cationic peptides could be accommodated within MtrD binding sites. Furthermore, we thought that MtrD-bound peptides lacking antibacterial action could sensitize bacteria to an antibiotic normally exported by the MtrCDE efflux pump or other similar RND-type pumps possessed by different Gram-negative bacteria. We now report the identification of a novel nonantimicrobial cyclic cationic antimicrobial peptide, which we termed CASP (cationic antibiotic-sensitizing peptide). By single-particle cryo-electron microscopy, we found that CASP binds within the periplasmic cleft region of MtrD using overlapping and distinct amino acid contact sites that interact with another cyclic peptide (colistin) or a linear human cationic antimicrobial peptide derived from human LL-37. While CASP could not sensitize Neisseria gonorrhoeae to an antibiotic (novobiocin) that is a substrate for RND pumps, it could do so against multiple Gram-negative, rod-shaped bacteria. We propose that CASP (or future derivatives) could serve as an adjuvant for the antibiotic treatment of certain Gram-negative infections previously thwarted by RND transporters. IMPORTANCE RND efflux pumps can export numerous antimicrobials that enter Gram-negative bacteria, and their action can reduce the efficacy of antibiotics and provide decreased susceptibility to various host antimicrobials. Here, we identified a cationic antibiotic-sensitizing peptide (CASP) that binds within the periplasmic cleft of an RND transporter protein (MtrD) produced by Neisseria gonorrhoeae. Surprisingly, CASP was able to render rod-shaped Gram-negative bacteria, but not gonococci, susceptible to an antibiotic that is a substrate for the gonococcal MtrCDE efflux pump. CASP (or its future derivatives) could be used as an adjuvant to treat infections for which RND efflux contributes to multidrug resistance.
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Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide. Antibiotics (Basel) 2022; 11:antibiotics11080984. [PMID: 35892374 PMCID: PMC9330635 DOI: 10.3390/antibiotics11080984] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/15/2022] [Accepted: 07/18/2022] [Indexed: 11/16/2022] Open
Abstract
Currently, there is a world-wide rise in antibiotic resistance causing burdens to individuals and public healthcare systems. At the same time drug development is lagging behind. Therefore, finding new ways of treating bacterial infections either by identifying new agents or combinations of drugs is of utmost importance. Additionally, if combination therapy is based on agents with different modes of action, resistance is less likely to develop. The synthesis of 21 fused pyrimidines and a structure-activity relationship study identified two 6-aryl-7H-pyrrolo [2,3-d] pyrimidin-4-amines with potent activity towards Staphylococcus aureus. The MIC-value was found to be highly dependent on a bromo or iodo substitution in the 4-benzylamine group and a hydroxyl in the meta or para position of the 6-aryl unit. The most active bromo and iodo derivatives had MIC of 8 mg/L. Interestingly, the most potent compounds experienced a four-fold lower MIC-value when they were combined with the antimicrobial peptide betatide giving MIC of 1–2 mg/L. The front runner bromo derivative also has a low activity towards 50 human kinases, including thymidylate monophosphate kinase, a putative antibacterial target.
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22
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Sajid MI, Lohan S, Kato S, Tiwari RK. Combination of Amphiphilic Cyclic Peptide [R4W4] and Levofloxacin against Multidrug-Resistant Bacteria. Antibiotics (Basel) 2022; 11:antibiotics11030416. [PMID: 35326879 PMCID: PMC8944500 DOI: 10.3390/antibiotics11030416] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023] Open
Abstract
Bacterial resistance is a growing global concern necessitating the discovery and development of antibiotics effective against the drug-resistant bacterial strain. Previously, we reported a cyclic antimicrobial peptide [R4W4] containing arginine (R) and tryptophan (W) with a MIC of 2.67 µg/mL (1.95 µM) against methicillin-resistant Staphylococcus aureus (MRSA). Herein, we investigated the cyclic peptides [R4W4] or linear (R4W4) and their conjugates (covalent or noncovalent) with levofloxacin (Levo) with the intent to improve their potency to target drug-resistant bacteria. The physical mixture of the Levo with the cyclic [R4W4] proved to be significantly effective against all strains of bacteria used in the study as compared to covalent conjugation. Furthermore, the checkerboard assay revealed the significant synergistic effect of the peptides against all studied strains except for the wild type S. aureus, in which the partial synergy was observed. The hemolysis assay revealed less cytotoxicity of the physical mixture of the Levo with [R4W4] (22%) as compared to [R4W4] alone (80%). The linear peptide (R4W4) and the cyclic [R4W4] demonstrated ~90% and 85% cell viability at 300 µg/mL in the triple-negative breast cancer cells (MDA-MB-231) and the normal kidney cells (HEK-293), respectively. Similar trends were also observed in the cell viability of Levo-conjugates on these cell lines. Furthermore, the time-kill kinetic study of the combination of [R4W4] and Levo demonstrate rapid killing action at 4 h for MRSA (ATCC BAA-1556) and 12 h for E. coli (ATCC BAA-2452), P. aeruginosa (ATCC BAA-1744), and K. pneumoniae (ATCC BAA-1705). These results provide the effectiveness of a combination of Levo with cyclic [R4W4] peptide, which may provide an opportunity to solve the intriguing puzzle of treating bacterial resistance.
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Affiliation(s)
- Muhammad Imran Sajid
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA; (M.I.S.); (S.L.); (S.K.)
- Faculty of Pharmacy, University of Central Punjab, Lahore 54000, Pakistan
| | - Sandeep Lohan
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA; (M.I.S.); (S.L.); (S.K.)
| | - Shun Kato
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA; (M.I.S.); (S.L.); (S.K.)
| | - Rakesh Kumar Tiwari
- Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA; (M.I.S.); (S.L.); (S.K.)
- Correspondence: ; Tel.: +1-714-516-5483; Fax: +1-714-516-5481
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Barros ALAN, Hamed A, Marani M, Moreira DC, Eaton P, Plácido A, Kato MJ, Leite JRSA. The Arsenal of Bioactive Molecules in the Skin Secretion of Urodele Amphibians. Front Pharmacol 2022; 12:810821. [PMID: 35095522 PMCID: PMC8795703 DOI: 10.3389/fphar.2021.810821] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/24/2021] [Indexed: 11/20/2022] Open
Abstract
Urodele amphibians (∼768 spp.), salamanders and newts, are a rich source of molecules with bioactive properties, especially those isolated from their skin secretions. These include pharmacological attributes, such as antimicrobial, antioxidant, vasoactive, immune system modulation, and dermal wound healing activities. Considering the high demand for new compounds to guide the discovery of new drugs to treat conventional and novel diseases, this review summarizes the characteristics of molecules identified in the skin of urodele amphibians. We describe urodele-derived peptides and alkaloids, with emphasis on their biological activities, which can be considered new scaffolds for the pharmaceutical industry. Although much more attention has been given to anurans, bioactive molecules produced by urodeles have the potential to be used for biotechnological purposes and stand as viable alternatives for the development of therapeutic agents.
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Affiliation(s)
- Ana L A N Barros
- Núcleo de Pesquisa em Morfologia e Imunologia Aplicada, NuPMIA, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil.,Programa de Pós-graduação em Medicina Tropical, PPGMT, Núcleo de Medicina Tropical, NMT, Faculdade de Medicina, UnB, Brasília, Brazil
| | - Abdelaaty Hamed
- Instituto de Química, IQ, Universidade de São Paulo, São Paulo, Brazil.,Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City-Cairo, Egypt
| | - Mariela Marani
- IPEEC-CONICET, Consejo Nacional de Investigaciones Científicas y Técnicas, Puerto Madryn, Argentina
| | - Daniel C Moreira
- Núcleo de Pesquisa em Morfologia e Imunologia Aplicada, NuPMIA, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil
| | - Peter Eaton
- LAQV/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Porto, Portugal.,Joseph Banks Laboratories, The Bridge, School of Chemistry, University of Lincoln, Lincoln, United Kingdom
| | - Alexandra Plácido
- LAQV/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Porto, Portugal.,Bioprospectum, Lda, UPTEC, Porto, Portugal
| | - Massuo J Kato
- Instituto de Química, IQ, Universidade de São Paulo, São Paulo, Brazil
| | - José Roberto S A Leite
- Núcleo de Pesquisa em Morfologia e Imunologia Aplicada, NuPMIA, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil.,Programa de Pós-graduação em Medicina Tropical, PPGMT, Núcleo de Medicina Tropical, NMT, Faculdade de Medicina, UnB, Brasília, Brazil.,Bioprospectum, Lda, UPTEC, Porto, Portugal
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24
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Duong L, Gross SP, Siryaporn A. Developing Antimicrobial Synergy With AMPs. FRONTIERS IN MEDICAL TECHNOLOGY 2022; 3:640981. [PMID: 35047912 PMCID: PMC8757689 DOI: 10.3389/fmedt.2021.640981] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 02/12/2021] [Indexed: 12/03/2022] Open
Abstract
Antimicrobial peptides (AMPs) have been extensively studied due to their vast natural abundance and ability to kill microbes. In an era critically lacking in new antibiotics, manipulating AMPs for therapeutic application is a promising option. However, bacterial pathogens resistant to AMPs remain problematic. To improve AMPs antimicrobial efficacy, their use in conjunction with other antimicrobials has been proposed. How might this work? AMPs kill bacteria by forming pores in bacterial membranes or by inhibiting bacterial macromolecular functions. What remains unknown is the duration for which AMPs keep bacterial pores open, and the extent to which bacteria can recover by repairing these pores. In this mini-review, we discuss various antimicrobial synergies with AMPs. Such synergies might arise if the antimicrobial agents helped to keep bacterial pores open for longer periods of time, prevented pore repair, perturbed bacterial intracellular functions at greater levels, or performed other independent bacterial killing mechanisms. We first discuss combinations of AMPs, and then focus on histones, which have antimicrobial activity and co-localize with AMPs on lipid droplets and in neutrophil extracellular traps (NETs). Recent work has demonstrated that histones can enhance AMP-induced membrane permeation. It is possible that histones, histone fragments, and histone-like peptides could amplify the antimicrobial effects of AMPs, giving rise to antimicrobial synergy. If so, clarifying these mechanisms will thus improve our overall understanding of the antimicrobial processes and potentially contribute to improved drug design.
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Affiliation(s)
- Leora Duong
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, United States
| | - Steven P Gross
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United States.,Department of Physics & Astronomy, University of California, Irvine, Irvine, CA, United States
| | - Albert Siryaporn
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, United States.,Department of Physics & Astronomy, University of California, Irvine, Irvine, CA, United States
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25
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Xu B, Wu X, Gong Y, Cao J. IL-27 induces LL-37/CRAMP expression from intestinal epithelial cells: implications for immunotherapy of Clostridioides difficile infection. Gut Microbes 2022; 13:1968258. [PMID: 34432564 PMCID: PMC8405154 DOI: 10.1080/19490976.2021.1968258] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Clostridioides difficile infection is currently the leading cause of nosocomial antibiotic-associated diarrhea and pseudomembranous colitis worldwide. Cathelicidins, a major group of natural antimicrobial peptides, have antimicrobial and immunomodulatory activities in Clostridioides difficile infection. Here, we have shown that cytokine IL-27 induced human cathelicidin antimicrobial peptide (LL-37) expression in primary human colonic epithelial cells. IL-27 receptor-deficient mice had impaired expression of cathelicidin-related antimicrobial peptide (CRAMP, mouse homolog for human LL-37) after Clostridioides difficile infection, and restoration of CRAMP improved Clostridium difficile clearance and reduced mortality in IL-27 receptor-deficient mice after Clostridioides difficile challenge. In clinical samples from 119 patients with Clostridioides difficile infection, elevated levels of IL-27 were positively correlated with LL-37 in the sera and stools. These findings suggest that IL-27 may be involved in host immunity against Clostridioides difficile infection via induction of LL-37/CRAMP. Therefore, IL-27-LL-37 axis may be a valuable pathway in the development of immune-based therapy.
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Affiliation(s)
- Banglao Xu
- Department of Laboratory Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Xianan Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Gong
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ju Cao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China,CONTACT Ju Cao Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Road 1#, Yu Zhong District, Chongqing, China
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26
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Gubatan J, Holman DR, Puntasecca CJ, Polevoi D, Rubin SJS, Rogalla S. Antimicrobial peptides and the gut microbiome in inflammatory bowel disease. World J Gastroenterol 2021; 27:7402-7422. [PMID: 34887639 PMCID: PMC8613745 DOI: 10.3748/wjg.v27.i43.7402] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/13/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Antimicrobial peptides (AMP) are highly diverse and dynamic molecules that are expressed by specific intestinal epithelial cells, Paneth cells, as well as immune cells in the gastrointestinal (GI) tract. They play critical roles in maintaining tolerance to gut microbiota and protecting against enteric infections. Given that disruptions in tolerance to commensal microbiota and loss of barrier function play major roles in the pathogenesis of inflammatory bowel disease (IBD) and converge on the function of AMP, the significance of AMP as potential biomarkers and novel therapeutic targets in IBD have been increasingly recognized in recent years. In this frontier article, we discuss the function and mechanisms of AMP in the GI tract, examine the interaction of AMP with the gut microbiome, explore the role of AMP in the pathogenesis of IBD, and review translational applications of AMP in patients with IBD.
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Affiliation(s)
- John Gubatan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Redwood City, CA 94063, United States
| | - Derek R Holman
- Department of Radiology, Molecular Imaging Program at Stanford , Stanford University, Stanford , CA 94305, United States
| | | | - Danielle Polevoi
- Stanford University School of Medicine, Stanford University, Stanford, CA 94063, United States
| | - Samuel JS Rubin
- Stanford University School of Medicine, Stanford University, Stanford, CA 94063, United States
| | - Stephan Rogalla
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Redwood City, CA 94063, United States
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27
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Zhao J, Sugihara K. Analysis of PDA Dose Curves for the Extraction of Antimicrobial Peptide Properties. J Phys Chem B 2021; 125:12206-12213. [PMID: 34706534 DOI: 10.1021/acs.jpcb.1c07533] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
A mechanochromic polymer, polydiacetylene, changes color upon ligand binding, being a popular material in biosensing. However, whether it can also detect ligand functions in addition to binding is left understudied. In this work, we report that the polydiacetylene can be used to determine the net charges and the mode of actions (carpet model, toroidal pore model, etc.) of antimicrobial peptides and detergents via EC50 and Hill coefficients from the colorimetric response-dose curves. This opens a potential for high-throughput peptide screening by functions, which is difficult with the conventional methods.
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Affiliation(s)
- Jiangtao Zhao
- Department of Physical Chemistry, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva, Switzerland
| | - Kaori Sugihara
- Department of Physical Chemistry, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva, Switzerland.,Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba Meguro-Ku, Tokyo 153-8505, Japan
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28
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Ting DSJ, Li J, Verma CS, Goh ETL, Nubile M, Mastropasqua L, Said DG, Beuerman RW, Lakshminarayanan R, Mohammed I, Dua HS. Evaluation of Host Defense Peptide (CaD23)-Antibiotic Interaction and Mechanism of Action: Insights From Experimental and Molecular Dynamics Simulations Studies. Front Pharmacol 2021; 12:731499. [PMID: 34690770 PMCID: PMC8528955 DOI: 10.3389/fphar.2021.731499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 09/27/2021] [Indexed: 11/13/2022] Open
Abstract
Background/Aim: Host defense peptides (HDPs) have the potential to provide a novel solution to antimicrobial resistance (AMR) in view of their unique and broad-spectrum antimicrobial activities. We had recently developed a novel hybrid HDP based on LL-37 and human beta-defensin-2, named CaD23, which was shown to exhibit good in vivo antimicrobial efficacy against Staphylococcus aureus in a bacterial keratitis murine model. This study aimed to examine the potential CaD23-antibiotic synergism and the secondary structure and underlying mechanism of action of CaD23. Methods: Peptide-antibiotic interaction was evaluated against S. aureus, methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa using established checkerboard and time-kill assays. Fractional inhibitory concentration index (FICI) was calculated and interpreted as synergistic (FIC<0.5), additive (FIC between 0.5-1.0), indifferent (FIC between >1.0 and ≤4), or antagonistic (FIC>4). SYTOX green uptake assay was performed to determine the membrane-permeabilising action of CaD23. Molecular dynamics (MD) simulations were performed to evaluate the interaction of CaD23 with bacterial and mammalian mimetic membranes. Circular dichroism (CD) spectroscopy was also performed to examine the secondary structures of CaD23. Results: CaD23-amikacin and CaD23-levofloxacin combination treatment exhibited a strong additive effect against S. aureus SH1000 (FICI = 0.60-0.69) and MRSA43300 (FICI = 0.56-0.60) but an indifferent effect against P. aeruginosa (FIC = 1.03-1.15). CaD23 (at 25 μg/ml; 2xMIC) completely killed S. aureus within 30 min. When used at sub-MIC concentration (3.1 μg/ml; 0.25xMIC), it was able to expedite the antimicrobial action of amikacin against S. aureus by 50%. The rapid antimicrobial action of CaD23 was attributed to the underlying membrane-permeabilising mechanism of action, evidenced by the SYTOX green uptake assay and MD simulations studies. MD simulations revealed that cationicity, alpha-helicity, amphiphilicity and hydrophobicity (related to the Trp residue at C-terminal) play important roles in the antimicrobial action of CaD23. The secondary structures of CaD23 observed in MD simulations were validated by CD spectroscopy. Conclusion: CaD23 is a novel alpha-helical, membrane-active synthetic HDP that can enhance and expedite the antimicrobial action of antibiotics against Gram-positive bacteria when used in combination. MD simulations serves as a powerful tool in revealing the peptide secondary structure, dissecting the mechanism of action, and guiding the design and optimisation of HDPs.
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Affiliation(s)
- Darren Shu Jeng Ting
- Academic Ophthalmology, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,Department of Ophthalmology, Queen's Medical Centre, Nottingham, United Kingdom.,Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore, Singapore
| | - Jianguo Li
- Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore, Singapore.,Bioinformatics Institute (AStar), Singapore, Singapore
| | - Chandra S Verma
- Bioinformatics Institute (AStar), Singapore, Singapore.,School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.,Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Eunice T L Goh
- Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore, Singapore
| | - Mario Nubile
- Ophthalmic Clinic, University "G d'Annunzio" of Chieti-Pescara, Chieti, Italy
| | | | - Dalia G Said
- Academic Ophthalmology, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,Department of Ophthalmology, Queen's Medical Centre, Nottingham, United Kingdom
| | - Roger W Beuerman
- Anti-Infectives Research Group, Singapore Eye Research Institute, Singapore, Singapore
| | | | - Imran Mohammed
- Academic Ophthalmology, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Harminder S Dua
- Academic Ophthalmology, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,Department of Ophthalmology, Queen's Medical Centre, Nottingham, United Kingdom
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29
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Arthithanyaroj S, Chankhamhaengdecha S, Chaisri U, Aunpad R, Aroonnual A. Effective inhibition of Clostridioides difficile by the novel peptide CM-A. PLoS One 2021; 16:e0257431. [PMID: 34516580 PMCID: PMC8437281 DOI: 10.1371/journal.pone.0257431] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/31/2021] [Indexed: 11/24/2022] Open
Abstract
Clostridioides difficile infection is the most common cause of nosocomial and antibiotic-associated diarrhea. C. difficile treatment is increasingly likely to fail, and the recurrence rate is high. Antimicrobial peptides are considered an alternative treatment for many infectious diseases, including those caused by antibiotic resistant bacteria. In the present study, we identified a CM peptide, a hybrid of cecropin A and melittin, and its derivative which possesses potent antimicrobial activity against C. difficile strain 630. CM peptide exhibited antibacterial activity with minimum inhibitory concentration of 3.906 μg/ml (2.21 μM). A modified derivative of CM, CM-A, exhibited even greater activity with a minimum inhibitory concentration of 1.953 μg/ml (1.06 μM) and a minimum bactericidal concentration of 7.8125 μg/ml (4.24 μM), which indicates that CM-A peptide is more efficient than its parent peptide. A fluorescence-activated cell sorter analysis revealed that the membrane of C. difficile 630 could be an important target for CM-A. This peptide induced high levels of cell depolarization and cell permeability on C. difficile cell membrane. Moreover, electron microscopy imaging showed that CM-A interferes with the C. difficile cell membrane. Hence, the antimicrobial peptide CM-A may represent a promising novel approach for the treatment of C. difficile infections.
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Affiliation(s)
- Sirirak Arthithanyaroj
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | | | - Urai Chaisri
- Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Ratchaneewan Aunpad
- Graduate Program in Biomedical Sciences, Faculty of Allied Health Sciences, Thammasat University, Pathum Thani, Thailand
| | - Amornrat Aroonnual
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- * E-mail:
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30
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BING, a novel antimicrobial peptide isolated from Japanese medaka plasma, targets bacterial envelope stress response by suppressing cpxR expression. Sci Rep 2021; 11:12219. [PMID: 34108601 PMCID: PMC8190156 DOI: 10.1038/s41598-021-91765-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/25/2021] [Indexed: 12/16/2022] Open
Abstract
Antimicrobial peptides (AMPs) have emerged as a promising alternative to small molecule antibiotics. Although AMPs have previously been isolated in many organisms, efforts on the systematic identification of AMPs in fish have been lagging. Here, we collected peptides from the plasma of medaka (Oryzias latipes) fish. By using mass spectrometry, 6399 unique sequences were identified from the isolated peptides, among which 430 peptides were bioinformatically predicted to be potential AMPs. One of them, a thermostable 13-residue peptide named BING, shows a broad-spectrum toxicity against pathogenic bacteria including drug-resistant strains, at concentrations that presented relatively low toxicity to mammalian cell lines and medaka. Proteomic analysis indicated that BING treatment induced a deregulation of periplasmic peptidyl-prolyl isomerases in gram-negative bacteria. We observed that BING reduced the RNA level of cpxR, an upstream regulator of envelope stress responses. cpxR is known to play a crucial role in the development of antimicrobial resistance, including the regulation of genes involved in drug efflux. BING downregulated the expression of efflux pump components mexB, mexY and oprM in P. aeruginosa and significantly synergised the toxicity of antibiotics towards these bacteria. In addition, exposure to sublethal doses of BING delayed the development of antibiotic resistance. To our knowledge, BING is the first AMP shown to suppress cpxR expression in Gram-negative bacteria. This discovery highlights the cpxR pathway as a potential antimicrobial target.
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31
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Ridyard KE, Overhage J. The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent. Antibiotics (Basel) 2021; 10:antibiotics10060650. [PMID: 34072318 PMCID: PMC8227053 DOI: 10.3390/antibiotics10060650] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
The rise in antimicrobial resistant bacteria threatens the current methods utilized to treat bacterial infections. The development of novel therapeutic agents is crucial in avoiding a post-antibiotic era and the associated deaths from antibiotic resistant pathogens. The human antimicrobial peptide LL-37 has been considered as a potential alternative to conventional antibiotics as it displays broad spectrum antibacterial and anti-biofilm activities as well as immunomodulatory functions. While LL-37 has shown promising results, it has yet to receive regulatory approval as a peptide antibiotic. Despite the strong antimicrobial properties, LL-37 has several limitations including high cost, lower activity in physiological environments, susceptibility to proteolytic degradation, and high toxicity to human cells. This review will discuss the challenges associated with making LL-37 into a viable antibiotic treatment option, with a focus on antimicrobial resistance and cross-resistance as well as adaptive responses to sub-inhibitory concentrations of the peptide. The possible methods to overcome these challenges, including immobilization techniques, LL-37 delivery systems, the development of LL-37 derivatives, and synergistic combinations will also be considered. Herein, we describe how combination therapy and structural modifications to the sequence, helicity, hydrophobicity, charge, and configuration of LL-37 could optimize the antimicrobial and anti-biofilm activities of LL-37 for future clinical use.
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32
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Portelinha J, Duay SS, Yu SI, Heilemann K, Libardo MDJ, Juliano SA, Klassen JL, Angeles-Boza AM. Antimicrobial Peptides and Copper(II) Ions: Novel Therapeutic Opportunities. Chem Rev 2021; 121:2648-2712. [PMID: 33524257 DOI: 10.1021/acs.chemrev.0c00921] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The emergence of new pathogens and multidrug resistant bacteria is an important public health issue that requires the development of novel classes of antibiotics. Antimicrobial peptides (AMPs) are a promising platform with great potential for the identification of new lead compounds that can combat the aforementioned pathogens due to their broad-spectrum antimicrobial activity and relatively low rate of resistance emergence. AMPs of multicellular organisms made their debut four decades ago thanks to ingenious researchers who asked simple questions about the resistance to bacterial infections of insects. Questions such as "Do fruit flies ever get sick?", combined with pioneering studies, have led to an understanding of AMPs as universal weapons of the immune system. This review focuses on a subclass of AMPs that feature a metal binding motif known as the amino terminal copper and nickel (ATCUN) motif. One of the metal-based strategies of hosts facing a pathogen, it includes wielding the inherent toxicity of copper and deliberately trafficking this metal ion into sites of infection. The sudden increase in the concentration of copper ions in the presence of ATCUN-containing AMPs (ATCUN-AMPs) likely results in a synergistic interaction. Herein, we examine common structural features in ATCUN-AMPs that exist across species, and we highlight unique features that deserve additional attention. We also present the current state of knowledge about the molecular mechanisms behind their antimicrobial activity and the methods available to study this promising class of AMPs.
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Affiliation(s)
- Jasmin Portelinha
- Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States
| | - Searle S Duay
- Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States.,Chemistry Department, Adamson University, 900 San Marcelino Street, Ermita, Manila 1000, Philippines
| | - Seung I Yu
- Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Storrs, Connecticut 06269, United States
| | - Kara Heilemann
- Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States
| | - M Daben J Libardo
- Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States
| | - Samuel A Juliano
- Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States
| | - Jonathan L Klassen
- Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Storrs, Connecticut 06269, United States
| | - Alfredo M Angeles-Boza
- Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States.,Institute of Material Science, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States
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Melo-Braga MN, De Marco Almeida F, Dos Santos DM, de Avelar Júnior JT, Dos Reis PVM, de Lima ME. Antimicrobial Peptides From Lycosidae (Sundevall, 1833) Spiders. Curr Protein Pept Sci 2021; 21:527-541. [PMID: 31951167 DOI: 10.2174/1389203721666200116091911] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 12/31/2019] [Accepted: 12/31/2019] [Indexed: 01/27/2023]
Abstract
Antimicrobial peptides (AMPs) have been found in all organism taxa and may play an essential role as a host defense system. AMPs are organized in various conformations, such as linear peptides, disulfide bond-linked peptides, backbone-linked peptides and circular peptides. AMPs apparently act primarily on the plasma membrane, although an increasing number of works have shown that they may also target various intracellular sites. Spider venoms are rich sources of biomolecules that show several activities, including modulation or blockage of ion channels, anti-insect, anti-cancer, antihypertensive and antimicrobial activities, among others. In spider venoms from the Lycosidae family there are many linear AMPs with a wide range of activities against several microorganisms. Due to these singular activities, some Lycosidae AMPs have been modified to improve or decrease desirable or undesirable effects, respectively. Such modifications, especially with the aim of increasing their antibiotic activity, have led to the filing of many patent applications. This review explores the abundance of Lycosidae venom AMPs and some of their derivatives, and their use as new drug models.
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Affiliation(s)
- Marcella Nunes Melo-Braga
- Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Flávia De Marco Almeida
- Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Joaquim Teixeira de Avelar Júnior
- Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Pablo Victor Mendes Dos Reis
- Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Maria Elena de Lima
- Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.,Santa Casa-Belo Horizonte: Ensino e Pesquisa, Belo Horizonte, MG, Brazil
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Faecal microbiota transplantation for Clostridioides difficile: mechanisms and pharmacology. Nat Rev Gastroenterol Hepatol 2021; 18:67-80. [PMID: 32843743 DOI: 10.1038/s41575-020-0350-4] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/07/2020] [Indexed: 12/14/2022]
Abstract
Faecal microbiota transplantation (FMT) has emerged as a remarkably successful treatment for recurrent Clostridioides difficile infection that cannot be cured with antibiotics alone. Understanding the complex biology and pathogenesis of C. difficile infection, which we discuss in this Perspective, is essential for understanding the potential mechanisms by which FMT cures this disease. Although FMT has already entered clinical practice, different microbiota-based products are currently in clinical trials and are vying for regulatory approval. However, all these therapeutics belong to an entirely new class of agents that require the development of a new branch of pharmacology. Characterization of microbiota therapeutics uses novel and rapidly evolving technologies and requires incorporation of microbial ecology concepts. Here, we consider FMT within a pharmacological framework, including its essential elements: formulation, pharmacokinetics and pharmacodynamics. From this viewpoint, multiple gaps in knowledge become apparent, identifying areas that require systematic research. This knowledge is needed to help clinical providers use microbiota therapeutics appropriately and to facilitate development of next-generation microbiota products with improved safety and efficacy. The discussion here is limited to FMT as a representative of microbiota therapeutics and recurrent C. difficile as the indication; however, consideration of the intrinsic basic principles is relevant to this entire class of microbiota-based therapeutics.
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Zong X, Fu J, Xu B, Wang Y, Jin M. Interplay between gut microbiota and antimicrobial peptides. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2020; 6:389-396. [PMID: 33364454 PMCID: PMC7750803 DOI: 10.1016/j.aninu.2020.09.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 12/19/2022]
Abstract
The gut microbiota is comprised of a diverse array of microorganisms that interact with immune system and exert crucial roles for the health. Changes in the gut microbiota composition and functionality are associated with multiple diseases. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Major players in this scenario are antimicrobial peptides (AMP), which belong to an ancient defense system found in all organisms and participate in a preservative co-evolution with a complex microbiome. Particularly increasing interactions between AMP and microbiota have been found in the gut. Here, we focus on the mechanisms by which AMP help to maintain a balanced microbiota and advancing our understanding of the circumstances of such balanced interactions between gut microbiota and host AMP. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota, which should have therapeutic implications for different intestinal disorders.
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Affiliation(s)
- Xin Zong
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jie Fu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bocheng Xu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yizhen Wang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Mingliang Jin
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
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Drab E, Sugihara K. Cooperative Function of LL-37 and HNP1 Protects Mammalian Cell Membranes from Lysis. Biophys J 2020; 119:2440-2450. [PMID: 33157121 DOI: 10.1016/j.bpj.2020.10.031] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 10/08/2020] [Indexed: 01/10/2023] Open
Abstract
LL-37, cleaved from human cathelicidin, and human neutrophil peptide-1 (HNP1) from the defensin family are antimicrobial peptides that are occasionally co-released from neutrophils, which synergistically kill bacteria. We report that this couple presents another type of cooperativity against host eukaryotic cells, in which they antagonistically minimize cytotoxicity by protecting membranes from lysis. Our results describe the potential of the LL-37/HNP1 cooperativity that switches from membrane-destructive to membrane-protective functions, depending on whether the target is an enemy or a host.
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Affiliation(s)
- Ewa Drab
- Department of Physical Chemistry, University of Geneva, Geneva, Switzerland
| | - Kaori Sugihara
- Institute of Industrial Science, The University of Tokyo, Tokyo, Japan; Department of Physical Chemistry, University of Geneva, Geneva, Switzerland.
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Development of Antimicrobial Peptides from Amphibians. Antibiotics (Basel) 2020; 9:antibiotics9110772. [PMID: 33158031 PMCID: PMC7692786 DOI: 10.3390/antibiotics9110772] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
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Hitt SJ, Bishop BM, van Hoek ML. Komodo-dragon cathelicidin-inspired peptides are antibacterial against carbapenem-resistant Klebsiella pneumoniae. J Med Microbiol 2020; 69:1262-1272. [DOI: 10.1099/jmm.0.001260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction.The rise of carbapenem-resistant enterobacteriaceae (CRE) is a growing crisis that requires development of novel therapeutics.Hypothesis.To this end, cationic antimicrobial peptides (CAMPs) represent a possible source of new potential therapeutics to treat difficult pathogens such as carbapenem-resistantKlebsiella pneumoniae(CRKP), which has gained resistance to many if not all currently approved antibiotics, making treatment difficult.Aim.To examine the anti-CRKP antimicrobial activity of the predicted cathelicidins derived fromVaranus komodoensis(Komodo dragon) as well as synthetic antimicrobial peptides that we created.Methodology.We determined the minimum inhibitory concentrations of the peptides against CRKP. We also characterized the abilities of these peptides to disrupt the hyperpolarization of the bacterial membrane as well as their ability to form pores in the membrane.Results.We did not observe significant anti-CRKP activity for the predicted native Komodo cathelicidin peptides. We found that the novel peptides DRGN-6,-7 and -8 displayed significant antimicrobial activity against CRKP with MICs of 4–8 µg ml−1. DRGN-6 peptide was the most effective peptide against CRKP. Unfortunately, these peptides showed higher than desired levels of hemolysis, althoughin vivotesting in the waxwormGalleria mellonellashowed no mortality associated with treatment by the peptide; however, CRKP-infected waxworms treated with peptide did not show an improvement in survival.Conclusion.Given the challenges of treating CRKP, identification of peptides with activity against it represents a promising avenue for further research. Given DRGN-6′s similar level of activity to colistin, DRGN-6 is a promising template for the development of novel antimicrobial peptide-based therapeutics.
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Luong HX, Thanh TT, Tran TH. Antimicrobial peptides - Advances in development of therapeutic applications. Life Sci 2020; 260:118407. [PMID: 32931796 PMCID: PMC7486823 DOI: 10.1016/j.lfs.2020.118407] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 02/07/2023]
Abstract
The severe infection is becoming a significant health problem which threaten the lives of patients and the safety and economy of society. In the way of finding new strategy, antimicrobial peptides (AMPs) - an important part of host defense family, emerged with tremendous potential. Up to date, huge numbers of AMPs has been investigated from both natural and synthetic sources showing not only the ability to kill microbial pathogens but also propose other benefits such as wound healing, anti-tumor, immune modulation. In this review, we describe the involvements of AMPs in biological systems and discuss the opportunity in developing AMPs for clinical applications. In the detail, their properties in antibacterial activity is followed by their application in some infection diseases and cancer. The key discussions are the approaches to improve biological activities of AMPs either by modifying chemical structure or incorporating into delivery systems. The new applications and perspectives for the future of AMPs would open the new era of their development.
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Affiliation(s)
- Huy Xuan Luong
- Faculty of Pharmacy, PHENIKAA University, Yen Nghia, Ha Dong, Hanoi 12116, Viet Nam; PHENIKAA Institute for Advanced Study (PIAS), PHENIKAA University, Hanoi 12116, Viet Nam.
| | - Tung Truong Thanh
- Faculty of Pharmacy, PHENIKAA University, Yen Nghia, Ha Dong, Hanoi 12116, Viet Nam; PHENIKAA Institute for Advanced Study (PIAS), PHENIKAA University, Hanoi 12116, Viet Nam.
| | - Tuan Hiep Tran
- Faculty of Pharmacy, PHENIKAA University, Yen Nghia, Ha Dong, Hanoi 12116, Viet Nam; PHENIKAA Research and Technology Institute (PRATI), A&A Green Phoenix Group JSC, No.167 Hoang Ngan, Trung Hoa, Cau Giay, Hanoi 11313, Viet Nam.
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Zheljazkov VD, Sikora V, Dincheva I, Kačániová M, Astatkie T, Semerdjieva IB, Latkovic D. Industrial, CBD, and Wild Hemp: How Different Are Their Essential Oil Profile and Antimicrobial Activity? Molecules 2020; 25:molecules25204631. [PMID: 33053634 PMCID: PMC7587197 DOI: 10.3390/molecules25204631] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 11/16/2022] Open
Abstract
Hemp (Cannabis sativa L.) is currently one of the most controversial and promising crops. This study compared nine wild hemp (C. sativa spp. spontanea V.) accessions with 13 registered cultivars, eight breeding lines, and one cannabidiol (CBD) hemp strain belonging to C. sativa L. The first three groups had similar main essential oil (EO) constituents, but in different concentrations; the CBD hemp had a different EO profile. The concentration of the four major constituents in the industrial hemp lines and wild hemp accessions varied as follows: β-caryophyllene 11-22% and 15.4-29.6%; α-humulene 4.4-7.6% and 5.3-11.9%; caryophyllene oxide 8.6-13.7% and 0.2-31.2%; and humulene epoxide 2, 2.3-5.6% and 1.2-9.5%, respectively. The concentration of CBD in the EO of wild hemp varied from 6.9 to 52.4% of the total oil while CBD in the EO of the registered cultivars varied from 7.1 to 25%; CBD in the EO of the breeding lines and in the CBD strain varied from 6.4 to 25% and 7.4 to 8.8%, respectively. The concentrations of δ9-tetrahydrocannabinol (THC) in the EO of the three groups of hemp were significantly different, with the highest concentration being 3.5%. The EO of wild hemp had greater antimicrobial activity compared with the EO of registered cultivars. This is the first report to show that significant amounts of CBD could be accumulated in the EO of wild and registered cultivars of hemp following hydro-distillation. The amount of CBD in the EO can be greater than that in the EO of the USA strain used for commercial production of CBD. Furthermore, this is among the first reports that show greater antimicrobial activity of the EO of wild hemp vs. the EO of registered cultivars. The results suggest that wild hemp may offer an excellent opportunity for future breeding and the selection of cultivars with a desirable composition of the EO and possibly CBD-rich EO production.
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Affiliation(s)
- Valtcho D. Zheljazkov
- Crop and Soil Science Department, 3050 SW Campus Way, Oregon State University, Corvallis, OR 97331, USA
- Correspondence: ; Tel.: +1-541-737-5877
| | - Vladimir Sikora
- Institute of Field and Vegetable Crops, Alternative Crops and Organic Production Department, Maksima Gorkog 30, 21000 Novi Sad, Serbia;
| | - Ivayla Dincheva
- Plant Genetic Research Group, Agrobioinstitute, Agricultural Academy, 8 “Dragan Tsankov” Blvd., 1164 Sofia, Bulgaria;
| | - Miroslava Kačániová
- Department of Fruit Science, Viticulture and Enology, Faculty of Horticulture and Landscape Engineering, Tr. A. Hlinku 2, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovakia;
- Department of Bioenergetics and Food Analysis, Institution of Food Technology and Nutrition, University of Rzeszow, Cwiklinskiej 1, 35-601 Rzeszow, Poland
| | - Tess Astatkie
- Department of Engineering, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, Canada;
| | - Ivanka B. Semerdjieva
- Department of Botany and Agrometeorology, Faculty of Agronomy, Agricultural University, 4000 Plovdiv, Bulgaria;
| | - Dragana Latkovic
- Department of Field and Vegetable Crops, University of Novi Sad, 21000 Novi Sad, Serbia;
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Ya’u Sabo Ajingi, Nujarin Jongruja. Antimicrobial Peptide Engineering: Rational Design, Synthesis, and Synergistic Effect. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2020. [DOI: 10.1134/s1068162020040044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Mercer DK, Torres MDT, Duay SS, Lovie E, Simpson L, von Köckritz-Blickwede M, de la Fuente-Nunez C, O'Neil DA, Angeles-Boza AM. Antimicrobial Susceptibility Testing of Antimicrobial Peptides to Better Predict Efficacy. Front Cell Infect Microbiol 2020; 10:326. [PMID: 32733816 PMCID: PMC7358464 DOI: 10.3389/fcimb.2020.00326] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022] Open
Abstract
During the development of antimicrobial peptides (AMP) as potential therapeutics, antimicrobial susceptibility testing (AST) stands as an essential part of the process in identification and optimisation of candidate AMP. Standard methods for AST, developed almost 60 years ago for testing conventional antibiotics, are not necessarily fit for purpose when it comes to determining the susceptibility of microorganisms to AMP. Without careful consideration of the parameters comprising AST there is a risk of failing to identify novel antimicrobials at a time when antimicrobial resistance (AMR) is leading the planet toward a post-antibiotic era. More physiologically/clinically relevant AST will allow better determination of the preclinical activity of drug candidates and allow the identification of lead compounds. An important consideration is the efficacy of AMP in biological matrices replicating sites of infection, e.g., blood/plasma/serum, lung bronchiolar lavage fluid/sputum, urine, biofilms, etc., as this will likely be more predictive of clinical efficacy. Additionally, specific AST for different target microorganisms may help to better predict efficacy of AMP in specific infections. In this manuscript, we describe what we believe are the key considerations for AST of AMP and hope that this information can better guide the preclinical development of AMP toward becoming a new generation of urgently needed antimicrobials.
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Affiliation(s)
| | - Marcelo D. T. Torres
- Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Penn Institute for Computational Science, and Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
| | - Searle S. Duay
- Department of Chemistry, Institute of Materials Science, University of Connecticut, Storrs, CT, United States
| | - Emma Lovie
- NovaBiotics Ltd, Aberdeen, United Kingdom
| | | | | | - Cesar de la Fuente-Nunez
- Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Penn Institute for Computational Science, and Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
| | | | - Alfredo M. Angeles-Boza
- Department of Chemistry, Institute of Materials Science, University of Connecticut, Storrs, CT, United States
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Martinenghi LD, Jønsson R, Lund T, Jenssen H. Isolation, Purification, and Antimicrobial Characterization of Cannabidiolic Acid and Cannabidiol from Cannabis sativa L. Biomolecules 2020; 10:E900. [PMID: 32545687 PMCID: PMC7355595 DOI: 10.3390/biom10060900] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/1970] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 12/11/2022] Open
Abstract
The emergence of multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) causes a major threat to public health due to its limited therapeutic options. There is an urgent need for the development of new effective antimicrobial agents and alternative strategies that are effective against resistant bacteria. The parallel legalization of cannabis and its products has fueled research into its many therapeutic avenues in many countries around the world. This study aimed at the development of a reliable method for the extraction, purification, characterization, and quantification of cannabidiolic acid (CBDA) and its decarboxylated form cannabidiol (CBD) present in the fiber type Cannabis sativa L. The two compounds were extracted by ethanol, purified on a C18 sep-pack column, and the extracts were analyzed by high performance liquid chromatography coupled with ultraviolet (UV)-vis and ESI-MS (electrospray ionization mass spectrometry) detection. The antimicrobial effect of CBDA and CBD was also evaluated. CBD displayed a substantial inhibitory effect on Gram-positive bacteria with minimal inhibitory concentrations ranging from 1 to 2 µg/mL. Time kill analysis and minimal bactericidal concentration revealed potential bactericidal activity of CBDA and CBD. While cannabinoids showed a significant antimicrobial effect on the Gram-positive S. aureus and Staphylococcus epidermidis, no activity was noticed on Gram-negative Escherichia coli and Pseudomonas aeruginosa. CBDA presented a two-fold lower antimicrobial activity than its decarboxylated form, suggesting that the antimicrobial pharmacophore of the analyzed cannabinoids falls in the ability for permeabilizing the bacterial cell membrane and acting as a detergent-like agent. A synergy test performed on MRSA with CBD and a range of antibiotics did not indicate a synergetic effect, but noteworthy no antagonist influence either. CBD and CBDA manifested low hemolytic activity on human red blood cells. Likewise, the safety of CBD toward human keratinocyte cells presents no toxicity at a concentration of up to seven-fold higher than the antibacterial minimal inhibitory concentration. Similarly, both CBD and CBDA are well tolerated by mammals, including humans, and conserve a safe value limits for blood-contacting drug development. Overall, CBD exhibited a strong antimicrobial effect against Gram-positive strains and could serve as an alternative drug for tackling MRSA.
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Affiliation(s)
| | | | | | - Håvard Jenssen
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (L.D.M.); (R.J.); (T.L.)
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Li J, Fernández-Millán P, Boix E. Synergism between Host Defence Peptides and Antibiotics Against Bacterial Infections. Curr Top Med Chem 2020; 20:1238-1263. [DOI: 10.2174/1568026620666200303122626] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/22/2020] [Accepted: 02/07/2020] [Indexed: 01/10/2023]
Abstract
Background:Antimicrobial resistance (AMR) to conventional antibiotics is becoming one of the main global health threats and novel alternative strategies are urging. Antimicrobial peptides (AMPs), once forgotten, are coming back into the scene as promising tools to overcome bacterial resistance. Recent findings have attracted attention to the potentiality of AMPs to work as antibiotic adjuvants.Methods:In this review, we have tried to collect the currently available information on the mechanism of action of AMPs in synergy with other antimicrobial agents. In particular, we have focused on the mechanisms of action that mediate the inhibition of the emergence of bacterial resistance by AMPs.Results and Conclusion:We find in the literature many examples where AMPs can significantly reduce the antibiotic effective concentration. Mainly, the peptides work at the bacterial cell wall and thereby facilitate the drug access to its intracellular target. Complementarily, AMPs can also contribute to permeate the exopolysaccharide layer of biofilm communities, or even prevent bacterial adhesion and biofilm growth. Secondly, we find other peptides that can directly block the emergence of bacterial resistance mechanisms or interfere with the community quorum-sensing systems. Interestingly, the effective peptide concentrations for adjuvant activity and inhibition of bacterial resistance are much lower than the required for direct antimicrobial action. Finally, many AMPs expressed by innate immune cells are endowed with immunomodulatory properties and can participate in the host response against infection. Recent studies in animal models confirm that AMPs work as adjuvants at non-toxic concentrations and can be safely administrated for novel combined chemotherapies.
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Affiliation(s)
- Jiarui Li
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autonoma de Barcelona, Cerdanyola del Valles, Spain
| | - Pablo Fernández-Millán
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autonoma de Barcelona, Cerdanyola del Valles, Spain
| | - Ester Boix
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autonoma de Barcelona, Cerdanyola del Valles, Spain
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Aryl-alkyl-lysines: Novel agents for treatment of C. difficile infection. Sci Rep 2020; 10:5624. [PMID: 32221399 PMCID: PMC7101335 DOI: 10.1038/s41598-020-62496-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 02/24/2020] [Indexed: 02/07/2023] Open
Abstract
Clostridium difficile infections (CDIs) are a growing health concern worldwide. The recalcitrance of C. difficile spores to currently available treatments and concomitant virulence of vegetative cells has made it imperative to develop newer modalities of treatment. Aryl-alkyl-lysines have been earlier reported to possess antimicrobial activity against pathogenic bacteria, fungi, and parasites. Their broad spectrum of activity is attributed to their ability to infiltrate microbial membranes. Herein, we report the activity of aryl-alkyl-lysines against C. difficile and associated pathogens. The most active compound NCK-10 displayed activity comparable to the clinically-used antibiotic vancomycin. Indeed, against certain C. difficile strains, NCK-10 was more active than vancomycin in vitro. Additionally, NCK-10 exhibited limited permeation across the intestinal tract as assessed via a Caco-2 bidirectional permeability assay. Overall, the findings suggest aryl-alkyl-lysines warrant further investigation as novel agents to treat CDI.
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Mücke PA, Maaß S, Kohler TP, Hammerschmidt S, Becher D. Proteomic Adaptation of Streptococcus pneumoniae to the Human Antimicrobial Peptide LL-37. Microorganisms 2020; 8:E413. [PMID: 32183275 PMCID: PMC7143398 DOI: 10.3390/microorganisms8030413] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 01/13/2023] Open
Abstract
Secreted antimicrobial peptides (AMPs) are an important part of the human innate immune system and prevent local and systemic infections by inhibiting bacterial growth in a concentration-dependent manner. In the respiratory tract, the cationic peptide LL-37 is one of the most abundant AMPs and capable of building pore complexes in usually negatively charged bacterial membranes, leading to the destruction of bacteria. However, the adaptation mechanisms of several pathogens to LL-37 are already described and are known to weaken the antimicrobial effect of the AMP, for instance, by repulsion, export or degradation of the peptide. This study examines proteome-wide changes in Streptococcus pneumoniae D39, the leading cause of bacterial pneumonia, in response to physiological concentrations of LL-37 by high-resolution mass spectrometry. Our data indicate that pneumococci may use some of the known adaptation mechanisms to reduce the effect of LL-37 on their physiology, too. Additionally, several proteins seem to be involved in resistance to AMPs which have not been related to this process before, such as the teichoic acid flippase TacF (SPD_1128). Understanding colonization- and infection-relevant adaptations of the pneumococcus to AMPs, especially LL-37, could finally uncover new drug targets to weaken the burden of this widespread pathogen.
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Affiliation(s)
- Pierre-Alexander Mücke
- Department of Microbial Proteomics, Institute of Microbiology, Center for Functional Genomics of Microbes, University of Greifswald, Felix-Hausdorff-Str. 8, 17489 Greifswald, Germany; (P.-A.M.); (S.M.)
| | - Sandra Maaß
- Department of Microbial Proteomics, Institute of Microbiology, Center for Functional Genomics of Microbes, University of Greifswald, Felix-Hausdorff-Str. 8, 17489 Greifswald, Germany; (P.-A.M.); (S.M.)
| | - Thomas P. Kohler
- Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Felix-Hausdorff-Str. 8, 17489 Greifswald, Germany; (T.P.K.); (S.H.)
| | - Sven Hammerschmidt
- Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Felix-Hausdorff-Str. 8, 17489 Greifswald, Germany; (T.P.K.); (S.H.)
| | - Dörte Becher
- Department of Microbial Proteomics, Institute of Microbiology, Center for Functional Genomics of Microbes, University of Greifswald, Felix-Hausdorff-Str. 8, 17489 Greifswald, Germany; (P.-A.M.); (S.M.)
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47
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Malanovic N, Marx L, Blondelle SE, Pabst G, Semeraro EF. Experimental concepts for linking the biological activities of antimicrobial peptides to their molecular modes of action. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183275. [PMID: 32173291 DOI: 10.1016/j.bbamem.2020.183275] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/09/2020] [Accepted: 03/10/2020] [Indexed: 02/07/2023]
Abstract
The search for novel compounds to combat multi-resistant bacterial infections includes exploring the potency of antimicrobial peptides and derivatives thereof. Complementary to high-throughput screening techniques, biophysical and biochemical studies of the biological activity of these compounds enable deep insight, which can be exploited in designing antimicrobial peptides with improved efficacy. This approach requires the combination of several techniques to study the effect of such peptides on both bacterial cells and simple mimics of their cell envelope, such as lipid-only vesicles. These efforts carry the challenge of bridging results across techniques and sample systems, including the proper choice of membrane mimics. This review describes some important concepts toward the development of potent antimicrobial peptides and how they translate to frequently applied experimental techniques, along with an outline of the biophysics pertaining to the killing mechanism of antimicrobial peptides.
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Affiliation(s)
- Nermina Malanovic
- University of Graz, Institute of Molecular Biosciences, Biophysics Division, Graz, Austria.
| | - Lisa Marx
- University of Graz, Institute of Molecular Biosciences, Biophysics Division, Graz, Austria
| | | | - Georg Pabst
- University of Graz, Institute of Molecular Biosciences, Biophysics Division, Graz, Austria
| | - Enrico F Semeraro
- University of Graz, Institute of Molecular Biosciences, Biophysics Division, Graz, Austria
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48
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Amadou Amani S, Lang ML. Bacteria That Cause Enteric Diseases Stimulate Distinct Humoral Immune Responses. Front Immunol 2020; 11:565648. [PMID: 33042146 PMCID: PMC7524877 DOI: 10.3389/fimmu.2020.565648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/18/2020] [Indexed: 12/12/2022] Open
Abstract
Bacterial enteric pathogens individually and collectively represent a serious global health burden. Humoral immune responses following natural or experimentally-induced infections are broadly appreciated to contribute to pathogen clearance and prevention of disease recurrence. Herein, we have compared observations on humoral immune mechanisms following infection with Citrobacter rodentium, the model for enteropathogenic Escherichia coli, Vibrio cholerae, Shigella species, Salmonella enterica species, and Clostridioides difficile. A comparison of what is known about the humoral immune responses to these pathogens reveals considerable variance in specific features of humoral immunity including establishment of high affinity, IgG class-switched memory B cell and long-lived plasma cell compartments. This article suggests that such variance could be contributory to persistent and recurrent disease.
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49
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Oludiran A, Courson DS, Stuart MD, Radwan AR, Poutsma JC, Cotten ML, Purcell EB. How Oxygen Availability Affects the Antimicrobial Efficacy of Host Defense Peptides: Lessons Learned from Studying the Copper-Binding Peptides Piscidins 1 and 3. Int J Mol Sci 2019; 20:E5289. [PMID: 31653020 PMCID: PMC6862162 DOI: 10.3390/ijms20215289] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
The development of new therapeutic options against Clostridioides difficile (C. difficile) infection is a critical public health concern, as the causative bacterium is highly resistant to multiple classes of antibiotics. Antimicrobial host-defense peptides (HDPs) are highly effective at simultaneously modulating the immune system function and directly killing bacteria through membrane disruption and oxidative damage. The copper-binding HDPs piscidin 1 and piscidin 3 have previously shown potent antimicrobial activity against a number of Gram-negative and Gram-positive bacterial species but have never been investigated in an anaerobic environment. Synergy between piscidins and metal ions increases bacterial killing aerobically. Here, we performed growth inhibition and time-kill assays against C. difficile showing that both piscidins suppress proliferation of C. difficile by killing bacterial cells. Microscopy experiments show that the peptides accumulate at sites of membrane curvature. We find that both piscidins are effective against epidemic C. difficile strains that are highly resistant to other stresses. Notably, copper does not enhance piscidin activity against C. difficile. Thus, while antimicrobial activity of piscidin peptides is conserved in aerobic and anaerobic settings, the peptide-copper interaction depends on environmental oxygen to achieve its maximum potency. The development of pharmaceuticals from HDPs such as piscidin will necessitate consideration of oxygen levels in the targeted tissue.
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Affiliation(s)
- Adenrele Oludiran
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529, USA.
| | - David S Courson
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529, USA.
| | - Malia D Stuart
- Biology Department, Palomar College, San Marcos, CA 92069, USA.
| | - Anwar R Radwan
- Department of Chemistry, College of William and Mary, Williamsburg, VA 23185, USA.
| | - John C Poutsma
- Department of Chemistry, College of William and Mary, Williamsburg, VA 23185, USA.
| | - Myriam L Cotten
- Department of Applied Science, College of William and Mary, Williamsburg, VA 23185, USA.
| | - Erin B Purcell
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529, USA.
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50
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de Freitas LM, Lorenzón EN, Cilli EM, de Oliveira KT, Fontana CR, Mang TS. Photodynamic and peptide-based strategy to inhibit Gram-positive bacterial biofilm formation. BIOFOULING 2019; 35:742-757. [PMID: 31550929 DOI: 10.1080/08927014.2019.1655548] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 07/25/2019] [Accepted: 08/07/2019] [Indexed: 06/10/2023]
Abstract
The self-produced extracellular polymeric matrix of biofilms renders them difficult to eliminate once they are established. This makes the inhibition of biofilm formation key to successful treatment of biofilm infection. Antimicrobial photodynamic therapy (aPDT) and antimicrobial peptides offer a new approach as antibiofilm strategies. In this study sub-lethal doses of aPDT (with chlorin-e6 (Ce6-PDT) or methylene blue (MB-PDT)) and the peptides AU (aurein 1.2 monomer) or (AU)2K (aurein 1.2 C-terminal dimer) were combined to evaluate their ability to prevent biofilm development by Enterococcus faecalis. Biofilm formation was assessed by resazurin reduction, confocal microscopy, and infrared spectroscopy. All treatments successfully prevented biofilm development. The (AU)2K dimer had a stronger effect, both alone and combined with aPDT, while the monomer AU had significant activity when combined with Ce6-PDT. Additionally, it is shown that the peptides bind to the lipoteichoic acid of the E. faecalis cell wall, pointing to a possible key mechanism of biofilm inhibition.
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Affiliation(s)
- Laura Marise de Freitas
- School of Pharmaceutical Sciences, Paulo State University (Unesp) , Araraquara , SP , Brazil
- Department of Oral and Maxillofacial Surgery, University at Buffalo School of Dental Medicine , Buffalo , NY , USA
| | - Esteban Nicolás Lorenzón
- Biological Sciences Institute, Biochemistry and Molecular biology department. Campus II Samambaia, Federal University of Goiás , Goiania , GO , Brazil
| | - Eduardo Maffud Cilli
- Institute of Chemistry, São Paulo State University (Unesp) , Araraquara , SP , Brazil
| | - Kleber Thiago de Oliveira
- Department of Chemistry, Bio-Organic Chemistry Laboratory, Federal University of São Carlos (UFSCar) , São Carlos , SP , Brazil
| | - Carla Raquel Fontana
- School of Pharmaceutical Sciences, Paulo State University (Unesp) , Araraquara , SP , Brazil
| | - Thomas S Mang
- Department of Oral and Maxillofacial Surgery, University at Buffalo School of Dental Medicine , Buffalo , NY , USA
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