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Raikwar G, Sharma S, Kumar D, Mohan S, Dahiya P. Exploring synergistic effects of Piper betle and Anethum graveolens essential oils with antibiotics against Methicillin-resistant Staphylococcus aureus: Insights from In silico targeting of PBP2a. Microb Pathog 2025; 203:107484. [PMID: 40097029 DOI: 10.1016/j.micpath.2025.107484] [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: 11/27/2024] [Revised: 02/21/2025] [Accepted: 03/14/2025] [Indexed: 03/19/2025]
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of infections worldwide, and remains challenging due to its resistance mechanisms. This study investigated potential synergistic antimicrobial activity of essential oils from Piper betle (PBEO) and Anethum graveolens (AGEO) in combination with conventional antibiotics against MRSA. Molecular docking simulations (MDS) were performed to explore the interactions with key components of essential oils and target protein Penicillin-Binding Protein 2a (PBP2a), which contributes to antibiotic resistance. Synergistic antibacterial effects were evaluated using clinical MRSA isolates and a reference strain, through broth microdilution, checkerboard, and time-kill assays. Amongst all the combinations tested, antibiotic tetracycline exhibited synergistic (FICI <0.5) and additive (FICI >0.5 < 1) interactions for both essential oils. Time-kill confirmed essential oil-antibiotics enhanced anti-MRSA activity when compared to their individual effects over 24 h. MDS showed strong interactions with major components of PBEO and the allosteric site of PBP2a, when compared to the components of AGEO. In silico findings from the study showed molecular interactions underlying the antimicrobial effects, supporting experimental data and highlighting PBEO and AGEO with tetracycline as promising anti-MRSA therapeutic candidates.
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Affiliation(s)
- Geetanjali Raikwar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida Sector-125, Uttar Pradesh, 201303, India
| | - Soumya Sharma
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida Sector-125, Uttar Pradesh, 201303, India
| | - Dharmender Kumar
- Department of Biotechnology, Deenbandhu Chhotu Ram University of Science &Technology Murthal, Sonipat, Haryana, 131309, India
| | - Sumedha Mohan
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida Sector-125, Uttar Pradesh, 201303, India.
| | - Praveen Dahiya
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida Sector-125, Uttar Pradesh, 201303, India.
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2
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Gutheil WG. Checkerboard synergistic data analysis using a Hill function-based approach. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.05.636765. [PMID: 39975223 PMCID: PMC11839125 DOI: 10.1101/2025.02.05.636765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
This study presents a checkerboard data analysis approach using a Hill function (y = 1/(1+(x/K)n) to fit each column and row of checkerboard assay data. Column fits give a K (MIC) value in units of row concentration for each column antibiotic concentration (MIC_row vs [Col]), and row fits give an MIC_col value for each row antibiotic (MIC_row vs [Row]). Since the corresponding row and column concentrations are themselves MICs, this provides two sets of MIC vs MIC data pairs which can be plotted together as an isobologram. These MIC_A vs MIC_B values can be subjected to a second round of Hill function fitting, separately in x-y and y-x directions. Finally, a fit based on overlapping Hill functions is developed that allows x-y and y-x dimension fits to be performed simultaneously. Formula for fractional inhibitory concentrations (FICIs) as a function of fit parameters, and other features of these curves, are derived. This analysis also provides "n" (steepness) values from column and row fits, which are themselves dependent on the other antibiotic concentration and can be exceptionally, as in the case of ceftobiprole alone (n>10). This synergistic checkerboard analysis approach is implemented in MATLAB, which performs the fits and provides statistics variable values and alternative models significance.
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Affiliation(s)
- William G. Gutheil
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA
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3
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Dai C, Liu Y, Lv F, Cheng P, Qu S. An alternative approach to combat multidrug-resistant bacteria: new insights into traditional Chinese medicine monomers combined with antibiotics. ADVANCED BIOTECHNOLOGY 2025; 3:6. [PMID: 39918653 PMCID: PMC11805748 DOI: 10.1007/s44307-025-00059-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/11/2025]
Abstract
Antibiotic treatment is crucial for controlling bacterial infections, but it is greatly hindered by the global prevalence of multidrug-resistant (MDR) bacteria. Although traditional Chinese medicine (TCM) monomers have shown high efficacy against MDR infections, the inactivation of bacteria induced by TCM is often incomplete and leads to infection relapse. The synergistic combination of TCM and antibiotics emerges as a promising strategy to mitigate the limitations inherent in both treatment modalities when independently administered. This review begins with a succinct exploration of the molecular mechanisms such as the antibiotic resistance, which informs the antibiotic discovery efforts. We subsequently provide an overview of the therapeutic effects of TCM/antibiotic combinations that have been developed. Finally, the factors that affect the therapeutic outcomes of these combinations and their underlying molecular mechanisms are systematically summarized. This overview offers insights into alternative strategies to treat clinical infections associated with MDR bacteria and the development of novel TCM/antibiotic combination therapies, with the goal of guiding their appropriate usage and further development.
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Affiliation(s)
- Cunchun Dai
- Animal-Derived Food Safety Innovation Team, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
- College of Materials and Chemistry, Anhui Agricultural University, Hefei, 230036, China
| | - Ying Liu
- College of Materials and Chemistry, Anhui Agricultural University, Hefei, 230036, China
| | - Fan Lv
- College of Materials and Chemistry, Anhui Agricultural University, Hefei, 230036, China
| | - Ping Cheng
- Animal-Derived Food Safety Innovation Team, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China.
| | - Shaoqi Qu
- Animal-Derived Food Safety Innovation Team, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China.
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4
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Dai J, Li Q, Li Z, Zang Z, Luo Y, Zhou C. Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial Agents. Molecules 2025; 30:243. [PMID: 39860113 PMCID: PMC11767251 DOI: 10.3390/molecules30020243] [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: 11/29/2024] [Revised: 01/02/2025] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
The overprescription of antibiotics in medicine and agriculture has accelerated the development and spread of antibiotic resistance in bacteria, which severely limits the arsenal available to clinicians for treating bacterial infections. This work discovered a new class of heteroarylcyanovinyl quinazolones and quinazolone pyridiniums to surmount the increasingly severe bacterial resistance. Bioactive assays manifested that the highly active compound 19a exhibited strong inhibition against MRSA and Escherichia coli with extremely low MICs of 0.5 μg/mL, being eightfold more active than that of norfloxacin (MICs = 4 μg/mL). The highly active 19a with rapid bactericidal properties displayed imperceptible resistance development trends, negligible hemolytic toxicity, and effective biofilm inhibitory effects. Preliminary explorations on antibacterial mechanisms revealed that compound 19a could cause membrane damage, embed in intracellular DNA to hinder bacterial DNA replication, and induce metabolic dysfunction. Surprisingly, active 19a was found to trigger the conformational change in PBP2a of MRSA to open the active site, which might account for its high inhibition against MRSA. In addition, the little effect of molecule 19a on the production of reactive oxygen species indicated that bacterial death was not caused by oxidative stress. The above comprehensive analyses highlighted the large potential of quinazolone pyridiniums as multitargeting broad-spectrum antibacterial agents.
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Affiliation(s)
- Jie Dai
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
| | - Qianyue Li
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
| | - Ziyi Li
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
| | - Zhonglin Zang
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
| | - Yan Luo
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Chenghe Zhou
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
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Nguyen DD, Duong TH, Nguyen TP, Nguyen HT, Nguyen CH. Antibacterial Potential of Ethyl 3,5-Dibromoorsellinate, a Derivative of Diphenyl Ethers from Graphis handelii, against Methicillin-Resistant Staphylococcus aureus. ACS OMEGA 2024; 9:50012-50023. [PMID: 39713661 PMCID: PMC11656388 DOI: 10.1021/acsomega.4c09518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/14/2024] [Accepted: 11/20/2024] [Indexed: 12/24/2024]
Abstract
Staphylococcus aureus is a human pathogen responsible for a variety of diseases, from skin, soft tissue, and lung infections to severe cases such as meningitis, infective endocarditis, and bacteremia. The high level of antibiotic resistance in these pathogens, exemplified by methicillin-resistant Staphylococcus aureus (MRSA), necessitates the development of effective antibiotics. Thus, this work introduced the chemical synthesis of ethyl 3,5-dibromoorsellinate, a derivative of ethyl orsellinate from the lichen mycobiont of Graphis handelii, and its effectiveness against MRSA was assessed. Results showed that ethyl 3,5-dibromoorsellinate efficiently inhibited MRSA with a minimum inhibitory concentration (MIC) of 4 μg/mL, and the time-kill analysis showed the bactericidal effect of ethyl 3,5-dibromoorsellinate on MRSA at 8× MIC after 24 h. The compound also exhibited selective activity against MRSA compared with the human cell line, with a selectivity index of 12.5-fold. While ethyl 3,5-dibromoorsellinate exhibited an indifferent effect with ampicillin, this compound demonstrated antagonistic effects with kanamycin in the synergistic assessment. Additionally, ethyl 3,5-dibromoorsellinate demonstrated antibiofilm activity against MRSA starting from 0.25× MIC. The molecular docking investigation illustrated that ethyl 3,5-dibromoorsellinate binds with the penicillin-binding protein 2A of MRSA with a free energy of -42.5 to -45.7 kcal/mol. Given its promising antibacterial activities, ethyl 3,5-dibromoorsellinate warrants further investigation as a potential antibiotic option against MRSA.
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Affiliation(s)
- Dao Dinh Nguyen
- Faculty of
Biology-Biotechnology, University of Science, Vietnam National University Ho Chi Minh City, 227 Nguyen Van Cu, District 5, Ho Chi Minh City 749000, Vietnam
| | - Thuc-Huy Duong
- Department
of Chemistry, Ho Chi Minh City University
of Education, 280 An Duong Vuong, District 5, Ho Chi Minh
City 748342, Vietnam
| | - Thi-Phuong Nguyen
- NTT Hi-Tech
Institute, Nguyen Tat Thanh University, 300A Nguyen Tat Thanh, District
4, Ho Chi Minh City 700000, Vietnam
| | - Huy Truong Nguyen
- Faculty of
Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
| | - Chuong Hoang Nguyen
- Faculty of
Biology-Biotechnology, University of Science, Vietnam National University Ho Chi Minh City, 227 Nguyen Van Cu, District 5, Ho Chi Minh City 749000, Vietnam
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Ge R, Zhao H, Tang Q, Chandarajoti K, Bai H, Wang X, Zhang K, Ye W, Han X, Wang C, Zhou W. A novel α-mangostin derivative synergistic to antibiotics against MRSA with unique mechanisms. Microbiol Spectr 2024; 12:e0163124. [PMID: 39508612 PMCID: PMC11619392 DOI: 10.1128/spectrum.01631-24] [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: 07/05/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading cause of hospital-acquired infections, often linked to complicated treatments, increased mortality risk, and significant cost burdens. Several antibacterial agents have been developed to address MRSA resistance. In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized α-mangostin (α-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. α-MG-4, featuring an allyl group at C3 of the lead compound α-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although α-MG-4 alone was ineffective against MRSA2, it exhibited an optimal synergistic ratio in vitro when combined with these antibiotics. This significant synergistic antibacterial effect was further confirmed in vivo using a mouse skin abscess model. Additionally, the synergistic mechanisms revealed that α-MG-4 was associated with changes in membrane permeability and inhibition of the MepA and NorA genes, which encode the efflux pumps of MRSA2. α-MG-4 also inhibited PBP2a expression, potentially by occupying a crucial binding site in a dose-dependent manner.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA)'s resistance to multiple antibiotics poses significant health and safety concerns. A novel α-mangostin (α-MG) derivative, α-MG-4, was first identified as a xanthone-based PBP2a inhibitor that reverses MRSA2 resistance to penicillin. The synergistic antibacterial effects of α-MG-4 were linked to increased cell membrane permeability and the inhibition of genes involved in efflux pump function.
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Affiliation(s)
- Rile Ge
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Haiyan Zhao
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China
| | - Qun Tang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Kasemsiri Chandarajoti
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand
- Drug Delivery System Excellence Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Han Bai
- Department of Clinical Pharmacy, College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Xiaoyang Wang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Key laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Keyu Zhang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Key laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Wenchong Ye
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Key laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Xiangan Han
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Chunmei Wang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Key laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Wen Zhou
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Key laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
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7
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Faragó T, Mészáros R, Wéber E, Palkó M. Synthesis and Docking Studies of Novel Spiro[5,8-methanoquinazoline-2,3'-indoline]-2',4-dione Derivatives. Molecules 2024; 29:5112. [PMID: 39519753 PMCID: PMC11547464 DOI: 10.3390/molecules29215112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
In this study, a set of spiro[5,8-methanoquinazoline-2,3'-indoline]-2',4-dione derivatives 3a-p were synthesized starting from unsubstituted and N-methyl-substituted diendo- and diexo-2-aminonorbornene carboxamides, as well as various substituted isatins. The typical method involves a condensation reaction of alicyclic aminocarboxamide and isatin in the presence of a catalyst, using a solvent and an acceptable temperature. We developed a cost-effective and ecologically benign high-speed ball milling (HSBM), microwave irradiation (MW), and continuous flow (CF) technique to synthesize spiroquinazolinone molecule 3a. The structures of the synthesized compounds 3a-p were determined using 1D and 2D NMR spectroscopies. Furthermore, docking studies and absorption, distribution, metabolism, and toxicity (ADMET) predictions were used in this work. In agreement with the corresponding features found in the case of both the SARS-CoV-2 main protease (RCSB Protein Data Bank: 6LU7) and human mast cell tryptase (RCSB Protein Data Bank: 2ZA5) based on the estimated total energy and binding affinity, H bonds, and hydrophobicity in silico, compound 3d among our 3a-g, 3i-k, and 3m derivatives was found to be our top-rated compound.
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Affiliation(s)
- Tünde Faragó
- Institute of Pharmaceutical Chemistry, Interdisciplinary Excellence Center, Faculty of Pharmacy, University of Szeged, Eötvös utca 6, H-6720 Szeged, Hungary; (T.F.); (R.M.)
| | - Rebeka Mészáros
- Institute of Pharmaceutical Chemistry, Interdisciplinary Excellence Center, Faculty of Pharmacy, University of Szeged, Eötvös utca 6, H-6720 Szeged, Hungary; (T.F.); (R.M.)
| | - Edit Wéber
- Department of Medical Chemistry, Faculty of Medicine, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary;
- HUN-REN-SZTE Biomimetic Systems Research Group, Dóm tér 8, H-6720 Szeged, Hungary
| | - Márta Palkó
- Institute of Pharmaceutical Chemistry, Interdisciplinary Excellence Center, Faculty of Pharmacy, University of Szeged, Eötvös utca 6, H-6720 Szeged, Hungary; (T.F.); (R.M.)
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8
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de Oliveira Silva BK, do Monte ZS, Santos Costa EC, Silva RO, Souza NF, Barros Menezes RP, Scotti MT, Scotti L, de Souza Lima GM, de Melo SJ. Synergistic effect of new pyrimidine derivative with oxacilin against methicillin-resistant Staphylococcus aureus. Future Med Chem 2024; 16:1839-1852. [PMID: 39235081 PMCID: PMC11486029 DOI: 10.1080/17568919.2024.2385887] [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: 03/28/2024] [Accepted: 07/18/2024] [Indexed: 09/06/2024] Open
Abstract
Aim: This work aimed to synthesize a new pyrimidine PYB01 with potential application against antimicrobial resistance.Materials & methods: PYB01 was synthesized through condensation reaction between 3a and 3b. The antimicrobial evaluation was carried out using the microdilution method in Mueller-Hinton Agar and in silico predictions using different software.Results: PYB01 has moderate antibiotic activity and high capacity to efficiently modulate antibiotic resistance in Staphylococcus aureus. In silico evaluations demonstrated that PYB01 is probably an allosteric inhibitor of Protein Binding Penicilin 2a and modulates the action of oxacillin by decreasing the minimum inhibitory concentration by 64-times. PYB01 demonstrate a good pharmacokinetic profile and toxicological.Conclusion: PYB01 has great potential to go further in investigating its use against antimicrobial resistance.
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Affiliation(s)
- Bruna Kelly de Oliveira Silva
- Postgraduate Program in Pharmaceutical Sciences-Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235 – University City, Recife, PE, 50740-560, Brazil
| | - Zenaide Severina do Monte
- Postgraduate Program in Pharmaceutical Sciences-Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235 – University City, Recife, PE, 50740-560, Brazil
| | - Erick Caique Santos Costa
- Postgraduate Program in Biological Sciences, Federal University of Pernambuco, Recife, PE, 50740-560, Brazil
| | - Ricardo Oliveira Silva
- Department of Fundamental Chemistry, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235 – University City, Recife, PE, 50740-560, Brazil
| | - Natália Ferreira Souza
- Laboratory of Cheminformatics, Program of Natural & Synthetic Bioactive Products (PgPNSB), Health Sciences Center Federal University of Paraíba, Campus I Lot. Cidade Universitaria, João Pessoa, PB, 58051-900, Brazil
| | - Renata Priscila Barros Menezes
- Laboratory of Cheminformatics, Program of Natural & Synthetic Bioactive Products (PgPNSB), Health Sciences Center Federal University of Paraíba, Campus I Lot. Cidade Universitaria, João Pessoa, PB, 58051-900, Brazil
| | - Marcus Tullius Scotti
- Laboratory of Cheminformatics, Program of Natural & Synthetic Bioactive Products (PgPNSB), Health Sciences Center Federal University of Paraíba, Campus I Lot. Cidade Universitaria, João Pessoa, PB, 58051-900, Brazil
| | - Luciana Scotti
- Laboratory of Cheminformatics, Program of Natural & Synthetic Bioactive Products (PgPNSB), Health Sciences Center Federal University of Paraíba, Campus I Lot. Cidade Universitaria, João Pessoa, PB, 58051-900, Brazil
| | - Gláucia Manoella de Souza Lima
- Department of Antibiotic, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235 – University City, Recife, PE, 50740-560, Brazil
| | - Sebastião José de Melo
- Postgraduate Program in Pharmaceutical Sciences-Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235 – University City, Recife, PE, 50740-560, Brazil
- Postgraduate Program in Biological Sciences, Federal University of Pernambuco, Recife, PE, 50740-560, Brazil
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9
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Wang H, Wang C, Wang Z, Niu X. Active Discovery of the Allosteric Inhibitor Targeting Botrytis cinerea Chitinase Based on Neural Relational Inference for Food Preservation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:16128-16139. [PMID: 39003764 DOI: 10.1021/acs.jafc.4c03023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Currently, allosteric inhibitors have emerged as an effective strategy in the development of preservatives against the drug-resistant Botrytis cinerea (B. cinerea). However, their passively driven development efficiency has proven challenging to meet the practical demands. Here, leveraging the deep learning Neural Relational Inference (NRI) framework, we actively identified an allosteric inhibitor targeting B. cinerea Chitinase, namely, 2-acetonaphthone. 2-Acetonaphthone binds to the crucial domain of Chitinase, forming the strong interaction with the allosteric sites. Throughout the interaction process, 2-acetonaphthone diminished the overall connectivity of the protein, inducing conformational changes. These findings align with the results obtained from Chitinase activity experiments, revealing an IC50 value of 67.6 μg/mL. Moreover, 2-acetonaphthone exhibited outstanding anti-B. cinerea activity by inhibiting Chitinase. In the gray mold infection model, 2-acetonaphthone significantly extended the preservation time of cherry tomatoes, positioning it as a promising preservative for fruit storage.
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Affiliation(s)
- Hongsu Wang
- College of Food Science and Engineering, Jilin University, Changchun 130062, P.R. China
| | - Chenyang Wang
- College of Food Science and Engineering, Jilin University, Changchun 130062, P.R. China
| | - Ziyou Wang
- College of Food Science and Engineering, Jilin University, Changchun 130062, P.R. China
| | - Xiaodi Niu
- College of Food Science and Engineering, Jilin University, Changchun 130062, P.R. China
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10
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Manhas R, Rathore A, Havelikar U, Mahajan S, Gandhi SG, Mahapa A. Uncovering the potentiality of quinazoline derivatives against Pseudomonas aeruginosa with antimicrobial synergy and SAR analysis. J Antibiot (Tokyo) 2024; 77:365-381. [PMID: 38514856 DOI: 10.1038/s41429-024-00717-3] [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: 08/17/2023] [Revised: 02/10/2024] [Accepted: 02/27/2024] [Indexed: 03/23/2024]
Abstract
Antimicrobial resistance has emerged as a covert global health crisis, posing a significant threat to humanity. If left unaddressed, it is poised to become the foremost cause of mortality worldwide. Among the multitude of resistant bacterial pathogens, Pseudomonas aeruginosa, a Gram-negative, facultative bacterium, has been responsible for mild to deadly infections. It is now enlisted as a global critical priority pathogen by WHO. Urgent measures are required to combat this formidable pathogen, necessitating the development of novel anti-pseudomonal drugs. To confront this pressing issue, we conducted an extensive screening of 3561 compounds from the ChemDiv library, resulting in the discovery of potent anti-pseudomonal quinazoline derivatives. Among the identified compounds, IDD-8E has emerged as a lead molecule, exhibiting exceptional efficacy against P. aeruginosa while displaying no cytotoxicity. Moreover, IDD-8E demonstrated significant pseudomonal killing, disruption of pseudomonal biofilm and other anti-bacterial properties comparable to a well-known antibiotic rifampicin. Additionally, IDD-8E's synergy with different antibiotics further strengthens its potential as a powerful anti-pseudomonal agent. IDD-8E also exhibited significant antimicrobial efficacy against other ESKAPE pathogens. Moreover, we elucidated the Structure-Activity-Relationship (SAR) of IDD-8E targeting the essential WaaP protein in P. aeruginosa. Altogether, our findings emphasize the promise of IDD-8E as a clinical candidate for novel anti-pseudomonal drugs, offering hope in the battle against antibiotic resistance and its devastating impact on global health.
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Affiliation(s)
- Rakshit Manhas
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India
| | - Arti Rathore
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Ujwal Havelikar
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India
| | - Shavi Mahajan
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India
| | - Sumit G Gandhi
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Avisek Mahapa
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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11
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Geng X, Zhang ZD, Li YX, Hao RC, Yang YJ, Liu XW, Li JY. Fingolimod synergizes and reverses K. pneumoniae resistance to colistin. Front Microbiol 2024; 15:1396663. [PMID: 38873155 PMCID: PMC11169662 DOI: 10.3389/fmicb.2024.1396663] [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: 03/06/2024] [Accepted: 05/13/2024] [Indexed: 06/15/2024] Open
Abstract
Klebsiella pneumoniae (K. pneumoniae) infection and the rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. Polymyxin E (colistin), a group of cationic antimicrobial polypeptides, is currently one of the last resort treatment options against carbapenem-resistant Gram-negative pathogens. The effectiveness of colistin has been compromised due to its intensive use. This study found that fingolimod (FLD), a natural product derivative, exhibited a significant synergistic bactericidal effect on K. pneumoniae when combined with colistin, both in vitro and in vivo. The checkerboard method was employed to assess the in vitro synergistic effect of FLD with colistin. FLD enhanced the susceptibility of bacteria to colistin and lowered effectively minimum inhibitory concentrations (MIC) when compared to colistin MIC, and the fractional inhibitory concentrations (FIC) value was less than 0.3. The time-kill curve demonstrated that the combination treatment of FLD and colistin had significant bactericidal efficacy. The in vitro concurrent administration of colistin and FLD resulted in heightening membrane permeability, compromising cell integrity, diminishing membrane fluidity, and perturbing membrane homeostasis. They also induced alterations in membrane potential, levels of reactive oxygen species, and adenosine triphosphate synthesis, ultimately culminating in bacterial death. Moreover, the combination of FLD with colistin significantly influenced fatty acid metabolism. In the mouse infection model, the survival rate of mice injected with K. pneumoniae was significantly improved to 67% and pathological damage was significantly relieved with combination treatment of FLD and colistin when compared with colistin treatment. This study highlights the potential of FLD in combining with colistin for treating infections caused by MDR isolates of K. pneumoniae.
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Affiliation(s)
| | | | | | | | | | - Xi-Wang Liu
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou, China
| | - Jian-Yong Li
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou, China
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12
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Jiao F, Cui W, Wang P, Tong HHY, Guo J, Tao J. Synergistic inhibition mechanism of quinazolinone and piperacillin on penicillin-binding protein 2a: a promising approach for combating methicillin-resistant Staphylococcus aureus. J Biomol Struct Dyn 2024:1-13. [PMID: 38497736 DOI: 10.1080/07391102.2024.2330708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 03/09/2024] [Indexed: 03/19/2024]
Abstract
The production of penicillin-binding protein 2a (PBP2a), a cell wall synthesis protein, is primarily responsible for the high-level resistance observed in methicillin-resistant Staphylococcus aureus (MRSA). PBP2a exhibits a significantly reduced affinity for most β-lactam antibiotics owing to its tightly closed active site. Quinazolinones (QNE), a novel class of non-β-lactam antibiotics, could initiate the allosteric regulation of PBP2a, resulting in the opening of the initially closed active pocket. Based on our previous study, we have a basic understanding of the dual-site inhibitor ceftaroline (CFT) induced allosteric regulation of PBP2a. However, there are still limitations in the knowledge of how combining medicines, QNE and piperacillin (PIP), induce the allosteric response of PBP2a and inhibit its function. Herein, molecular dynamics (MD) simulations were performed to elucidate the intricate mechanisms underlying the combination mode of QNE and PIP. Our study successfully captured the opening process of the active pocket upon the binding of the QNE at the allosteric site, which alters the signaling pathways with a favorable transmission to the active site. Subsequent docking experiments with different conformational states of the active pocket indicated that all three inhibitors, PIP, QNE, and CFT, exhibited higher docking scores and more favorable docking poses to the open active pocket. These findings reveal the implied mechanism of QNE-mediated allostery underlying combination therapy and provide novel insights into developing innovative therapeutic modalities against MRSA.
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Affiliation(s)
- Fangfang Jiao
- Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China
| | - Weirong Cui
- Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China
| | - Pinkai Wang
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Henry H Y Tong
- Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China
| | - Jingjing Guo
- Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China
- Engineering Research Centre of Applied Technology on Machine Translation and Artificial Intelligence, Macao Polytechnic University, Macao, China
| | - Jun Tao
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, China
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13
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Jiao F, Bao Y, Li M, Zhang Y, Zhang F, Wang P, Tao J, Tong HHY, Guo J. Unraveling the mechanism of ceftaroline-induced allosteric regulation in penicillin-binding protein 2a: insights for novel antibiotic development against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2023; 67:e0089523. [PMID: 37971241 PMCID: PMC10720500 DOI: 10.1128/aac.00895-23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/11/2023] [Indexed: 11/19/2023] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) acquires high-level resistance against β-lactam antibiotics by expressing penicillin-binding protein 2a (PBP2a). PBP2a is a cell wall-synthesizing protein whose closed active site exhibits a reduced binding affinity toward β-lactam antibiotics. Ceftaroline (CFT), a fifth-generation cephalosporin, can effectively inhibit the PBP2a activity by binding to an allosteric site to trigger the active site opening, allowing a second CFT to access the active site. However, the essential mechanism behind the allosteric behavior of PBP2a remains unclear. Herein, computational simulations are employed to elucidate how CFT allosterically regulates the conformation and dynamics of the active site of PBP2a. While CFT stabilizes the allosteric domain surrounding it, it simultaneously enhances the dynamics of the catalytic domain. Specifically, the study successfully captured the opening process of the active pocket in the allosteric CFT-bound systems and discovered that CFT alters the potential signal-propagating pathways from the allosteric site to the active site. These findings reveal the implied mechanism of the CFT-mediated allostery in PBP2a and provide new insights into dual-site drug design or combination therapy against MRSA targeting PBP2a.
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Affiliation(s)
- Fangfang Jiao
- Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China
| | - Yiqiong Bao
- College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Mengrong Li
- College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Yan Zhang
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Feng Zhang
- College of Plant Protection, Nanjing Agricultural University, Nanjing, China
| | - Pinkai Wang
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jun Tao
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Henry H. Y. Tong
- Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China
| | - Jingjing Guo
- Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China
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14
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Ambade SS, Gupta VK, Bhole RP, Khedekar PB, Chikhale RV. A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA). Molecules 2023; 28:7008. [PMID: 37894491 PMCID: PMC10609489 DOI: 10.3390/molecules28207008] [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: 09/08/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
Staphylococcus aureus is a common human pathogen. Methicillin-resistant Staphylococcus aureus (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene PBP2a, which results in reduced susceptibility to β-lactam antibiotics, thus conferring resistance. PBP2a has a lower affinity for methicillin, allowing bacteria to maintain peptidoglycan biosynthesis, a core component of the bacterial cell wall. Consequently, even in the presence of methicillin or other antibiotics, bacteria can develop resistance. Due to genes responsible for resistance, S. aureus becomes MRSA. The fundamental premise of this resistance mechanism is well-understood. Given the therapeutic concerns posed by resistant microorganisms, there is a legitimate demand for novel antibiotics. This review primarily focuses on PBP2a scaffolds and the various screening approaches used to identify PBP2a inhibitors. The following classes of compounds and their biological activities are discussed: Penicillin, Cephalosporins, Pyrazole-Benzimidazole-based derivatives, Oxadiazole-containing derivatives, non-β-lactam allosteric inhibitors, 4-(3H)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycles (β-lactam antibiotics with 1,3-Bridges), Macrocycle-embedded β-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-β-lactam antibiotics, Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a. Additionally, we discuss the penicillin-binding protein, a crucial target in the MRSA cell wall. Various aspects of PBP2a, bacterial cell walls, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives on MRSA inhibitors are also explored.
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Affiliation(s)
- Shraddha S. Ambade
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440033, MH, India (P.B.K.)
| | - Vivek Kumar Gupta
- Department of Biochemistry, National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), Agra 282004, UP, India
| | - Ritesh P. Bhole
- Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, MH, India
- Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune 411018, MH, India
| | - Pramod B. Khedekar
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440033, MH, India (P.B.K.)
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15
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Bertonha AF, Silva CCL, Shirakawa KT, Trindade DM, Dessen A. Penicillin-binding protein (PBP) inhibitor development: A 10-year chemical perspective. Exp Biol Med (Maywood) 2023; 248:1657-1670. [PMID: 38030964 PMCID: PMC10723023 DOI: 10.1177/15353702231208407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023] Open
Abstract
Bacterial cell wall formation is essential for cellular survival and morphogenesis. The peptidoglycan (PG), a heteropolymer that surrounds the bacterial membrane, is a key component of the cell wall, and its multistep biosynthetic process is an attractive antibacterial development target. Penicillin-binding proteins (PBPs) are responsible for cross-linking PG stem peptides, and their central role in bacterial cell wall synthesis has made them the target of successful antibiotics, including β-lactams, that have been used worldwide for decades. Following the discovery of penicillin, several other compounds with antibiotic activity have been discovered and, since then, have saved millions of lives. However, since pathogens inevitably become resistant to antibiotics, the search for new active compounds is continuous. The present review highlights the ongoing development of inhibitors acting mainly in the transpeptidase domain of PBPs with potential therapeutic applications for the development of new antibiotic agents. Both the critical aspects of the strategy, design, and structure-activity relationships (SAR) are discussed, covering the main published articles over the last 10 years. Some of the molecules described display activities against main bacterial pathogens and could open avenues toward the development of new, efficient antibacterial drugs.
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Affiliation(s)
- Ariane F Bertonha
- Brazilian Biosciences National Laboratory (LNBio), CNPEM, Campinas 13084-971, Brazil
| | - Caio C L Silva
- Brazilian Biosciences National Laboratory (LNBio), CNPEM, Campinas 13084-971, Brazil
| | - Karina T Shirakawa
- Brazilian Biosciences National Laboratory (LNBio), CNPEM, Campinas 13084-971, Brazil
- Departamento de Genética, Evolução, Microbiologia e Imunologia, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-862, Brazil
| | - Daniel M Trindade
- Brazilian Biosciences National Laboratory (LNBio), CNPEM, Campinas 13084-971, Brazil
| | - Andréa Dessen
- Brazilian Biosciences National Laboratory (LNBio), CNPEM, Campinas 13084-971, Brazil
- Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS), F-38044 Grenoble, France
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16
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Hunashal Y, Kumar GS, Choy MS, D'Andréa ÉD, Da Silva Santiago A, Schoenle MV, Desbonnet C, Arthur M, Rice LB, Page R, Peti W. Molecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5. Nat Commun 2023; 14:4268. [PMID: 37460557 DOI: 10.1038/s41467-023-39966-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 07/06/2023] [Indexed: 07/20/2023] Open
Abstract
Penicillin-binding proteins (PBPs) are essential for the formation of the bacterial cell wall. They are also the targets of β-lactam antibiotics. In Enterococcus faecium, high levels of resistance to β-lactams are associated with the expression of PBP5, with higher levels of resistance associated with distinct PBP5 variants. To define the molecular mechanism of PBP5-mediated resistance we leveraged biomolecular NMR spectroscopy of PBP5 - due to its size (>70 kDa) a challenging NMR target. Our data show that resistant PBP5 variants show significantly increased dynamics either alone or upon formation of the acyl-enzyme inhibitor complex. Furthermore, these variants also exhibit increased acyl-enzyme hydrolysis. Thus, reducing sidechain bulkiness and expanding surface loops results in increased dynamics that facilitates acyl-enzyme hydrolysis and, via increased β-lactam antibiotic turnover, facilitates β-lactam resistance. Together, these data provide the molecular basis of resistance of clinical E. faecium PBP5 variants, results that are likely applicable to the PBP family.
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Affiliation(s)
- Yamanappa Hunashal
- Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA
| | - Ganesan Senthil Kumar
- Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA
- National Institute of Immunology, New Delhi, India
| | - Meng S Choy
- Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA
| | - Éverton D D'Andréa
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA
| | | | - Marta V Schoenle
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA
| | - Charlene Desbonnet
- Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Michel Arthur
- INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Louis B Rice
- Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Rebecca Page
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA
| | - Wolfgang Peti
- Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA.
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17
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Dai J, Battini N, Zang Z, Luo Y, Zhou C. Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a. Molecules 2023; 28:molecules28104240. [PMID: 37241983 DOI: 10.3390/molecules28104240] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Bacterial infections caused by methicillin-resistant Staphylococcus aureus have seriously threatened public health. There is an urgent need to propose an existing regimen to overcome multidrug resistance of MRSA. A unique class of novel anti-MRSA thiazolylketenyl quinazolinones (TQs) and their analogs were developed. Some synthesized compounds showed good bacteriostatic potency. Especially TQ 4 was found to exhibit excellent inhibition against MRSA with a low MIC of 0.5 μg/mL, which was 8-fold more effective than norfloxacin. The combination of TQ 4 with cefdinir showed stronger antibacterial potency. Further investigation revealed that TQ 4, with low hemolytic toxicity and low drug resistance, was not only able to inhibit biofilm formation but also could reduce MRSA metabolic activity and showed good drug-likeness. Mechanistic explorations revealed that TQ 4 could cause leakage of proteins by disrupting membrane integrity and block DNA replication by intercalated DNA. Furthermore, the synergistic antibacterial effect with cefdinir might be attributed to TQ 4 with the ability to induce PBP2a allosteric regulation of MRSA and further trigger the opening of the active site to promote the binding of cefdinir to the active site, thus inhibiting the expression of PBP2a, thereby overcoming MRSA resistance and significantly enhancing the anti-MRSA activity of cefdinir. A new strategy provided by these findings was that TQ 4, possessing both excellent anti-MRSA activity and allosteric effect of PBP2a, merited further development as a novel class of antibacterial agents to overcome increasingly severe MRSA infections.
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Affiliation(s)
- Jie Dai
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
| | - Narsaiah Battini
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
| | - Zhonglin Zang
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
| | - Yan Luo
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Chenghe Zhou
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
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18
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Dhanda G, Acharya Y, Haldar J. Antibiotic Adjuvants: A Versatile Approach to Combat Antibiotic Resistance. ACS OMEGA 2023; 8:10757-10783. [PMID: 37008128 PMCID: PMC10061514 DOI: 10.1021/acsomega.3c00312] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/21/2023] [Indexed: 06/13/2023]
Abstract
The problem of antibiotic resistance is on the rise, with multidrug-resistant strains emerging even to the last resort antibiotics. The drug discovery process is often stalled by stringent cut-offs required for effective drug design. In such a scenario, it is prudent to delve into the varying mechanisms of resistance to existing antibiotics and target them to improve antibiotic efficacy. Nonantibiotic compounds called antibiotic adjuvants which target bacterial resistance can be used in combination with obsolete drugs for an improved therapeutic regime. The field of "antibiotic adjuvants" has gained significant traction in recent years where mechanisms other than β-lactamase inhibition have been explored. This review discusses the multitude of acquired and inherent resistance mechanisms employed by bacteria to resist antibiotic action. The major focus of this review is how to target these resistance mechanisms by the use of antibiotic adjuvants. Different types of direct acting and indirect resistance breakers are discussed including enzyme inhibitors, efflux pump inhibitors, inhibitors of teichoic acid synthesis, and other cellular processes. The multifaceted class of membrane-targeting compounds with poly pharmacological effects and the potential of host immune-modulating compounds have also been reviewed. We conclude with providing insights about the existing challenges preventing clinical translation of different classes of adjuvants, especially membrane-perturbing compounds, and a framework about the possible directions which can be pursued to fill this gap. Antibiotic-adjuvant combinatorial therapy indeed has immense potential to be used as an upcoming orthogonal strategy to conventional antibiotic discovery.
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Affiliation(s)
- Geetika Dhanda
- Antimicrobial
Research Laboratory, New Chemistry Unit and School of Advanced
Materials, Jawaharlal Nehru Centre for Advanced
Scientific Research (JNCASR), Jakkur, Bengaluru 560064, Karnataka, India
| | - Yash Acharya
- Antimicrobial
Research Laboratory, New Chemistry Unit and School of Advanced
Materials, Jawaharlal Nehru Centre for Advanced
Scientific Research (JNCASR), Jakkur, Bengaluru 560064, Karnataka, India
| | - Jayanta Haldar
- Antimicrobial
Research Laboratory, New Chemistry Unit and School of Advanced
Materials, Jawaharlal Nehru Centre for Advanced
Scientific Research (JNCASR), Jakkur, Bengaluru 560064, Karnataka, India
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19
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Baran A, Kwiatkowska A, Potocki L. Antibiotics and Bacterial Resistance-A Short Story of an Endless Arms Race. Int J Mol Sci 2023; 24:ijms24065777. [PMID: 36982857 PMCID: PMC10056106 DOI: 10.3390/ijms24065777] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/10/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Despite the undisputed development of medicine, antibiotics still serve as first-choice drugs for patients with infectious disorders. The widespread use of antibiotics results from a wide spectrum of their actions encompassing mechanisms responsible for: the inhibition of bacterial cell wall biosynthesis, the disruption of cell membrane integrity, the suppression of nucleic acids and/or proteins synthesis, as well as disturbances of metabolic processes. However, the widespread availability of antibiotics, accompanied by their overprescription, acts as a double-edged sword, since the overuse and/or misuse of antibiotics leads to a growing number of multidrug-resistant microbes. This, in turn, has recently emerged as a global public health challenge facing both clinicians and their patients. In addition to intrinsic resistance, bacteria can acquire resistance to particular antimicrobial agents through the transfer of genetic material conferring resistance. Amongst the most common bacterial resistance strategies are: drug target site changes, increased cell wall permeability to antibiotics, antibiotic inactivation, and efflux pumps. A better understanding of the interplay between the mechanisms of antibiotic actions and bacterial defense strategies against particular antimicrobial agents is crucial for developing new drugs or drug combinations. Herein, we provide a brief overview of the current nanomedicine-based strategies that aim to improve the efficacy of antibiotics.
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Affiliation(s)
- Aleksandra Baran
- Department of Biotechnology, College of Natural Sciences, University of Rzeszów, Pigonia 1, 35-310 Rzeszow, Poland
| | - Aleksandra Kwiatkowska
- Institute of Physical Culture Studies, College of Medical Sciences, University of Rzeszów, ul. Towarnickiego 3, 35-959 Rzeszów, Poland
| | - Leszek Potocki
- Department of Biotechnology, College of Natural Sciences, University of Rzeszów, Pigonia 1, 35-310 Rzeszow, Poland
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20
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Ye J, Chen X. Current Promising Strategies against Antibiotic-Resistant Bacterial Infections. Antibiotics (Basel) 2022; 12:antibiotics12010067. [PMID: 36671268 PMCID: PMC9854991 DOI: 10.3390/antibiotics12010067] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022] Open
Abstract
Infections caused by antibiotic-resistant bacteria (ARB) are one of the major global health challenges of our time. In addition to developing new antibiotics to combat ARB, sensitizing ARB, or pursuing alternatives to existing antibiotics are promising options to counter antibiotic resistance. This review compiles the most promising anti-ARB strategies currently under development. These strategies include the following: (i) discovery of novel antibiotics by modification of existing antibiotics, screening of small-molecule libraries, or exploration of peculiar places; (ii) improvement in the efficacy of existing antibiotics through metabolic stimulation or by loading a novel, more efficient delivery systems; (iii) development of alternatives to conventional antibiotics such as bacteriophages and their encoded endolysins, anti-biofilm drugs, probiotics, nanomaterials, vaccines, and antibody therapies. Clinical or preclinical studies show that these treatments possess great potential against ARB. Some anti-ARB products are expected to become commercially available in the near future.
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21
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Guan S, Zhong L, Yu H, Wang L, Jin Y, Liu J, Xiang H, Yu H, Wang L, Wang D. Molecular docking and proteomics reveals the synergistic antibacterial mechanism of theaflavin with β-lactam antibiotics against MRSA. Front Microbiol 2022; 13:993430. [PMID: 36452924 PMCID: PMC9702817 DOI: 10.3389/fmicb.2022.993430] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 10/11/2022] [Indexed: 04/09/2024] Open
Abstract
Recurrent epidemics of methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) have illustrated that the effectiveness of antibiotics in clinical application is rapidly fading. A feasible approach is to combine natural products with existing antibiotics to achieve an antibacterial effect. In this molecular docking study, we found that theaflavin (TF) preferentially binds the allosteric site of penicillin-binding protein 2a (PBP2a), inducing the PBP2a active site to open, which is convenient for β-lactam antibiotics to treat MRSA infection, instead of directly exerting antibacterial activity at the active site. Subsequent TMT-labeled proteomics analysis showed that TF treatment did not significantly change the landscape of the S. aureus USA300 proteome. Checkerboard dilution tests and kill curve assays were performed to validate the synergistic effect of TF and ceftiofur, and the fractional inhibitory concentration index (FICI) was 0.1875. The antibacterial effect of TF combined with ceftiofur was better than that of single-drug treatment in vitro. In addition, TF effectively enhanced the activity of ceftiofur in a mouse model of MRSA-induced pneumonia. Our findings provide a potential therapeutic strategy to combine existing antibiotics with natural products to resolve the prevalent infections of multidrug-resistant pathogens.
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Affiliation(s)
- Shuhan Guan
- College of Animal Science, Jilin University, Changchun, China
| | - Ling Zhong
- College of Animal Science, Jilin University, Changchun, China
| | - Hangqian Yu
- College of Animal Science, Jilin University, Changchun, China
| | - Li Wang
- Changchun University of Chinese Medicine, Changchun, China
| | - Yajing Jin
- College of Animal Science, Jilin University, Changchun, China
| | - Jingyu Liu
- College of Animal Science, Jilin University, Changchun, China
| | - Hua Xiang
- College of Animal Medicine, Jilin Agricultural University, Changchun, China
| | - Hao Yu
- College of Animal Science, Jilin University, Changchun, China
| | - Lin Wang
- State Key Laboratory for Zoonotic Diseases, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Dacheng Wang
- College of Animal Science, Jilin University, Changchun, China
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22
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Ibezim A, Onuku R, Ottih C, Ezeonu I, Onoabedje E, Ramanathan K, Nwodo N. New sulphonamide-peptide hybrid molecules as potential PBP 2a ligands and methicillin resistant Staphylococcus aureus actives. J Biomol Struct Dyn 2022:1-11. [PMID: 35975581 DOI: 10.1080/07391102.2022.2111359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Penicillin binding protein 2a (PbP 2a) expression accounts for the insusceptibility of methicillin-resistant Staphylocuccus aureus (MRSA) to β-lactam antibiotics. Here we employed computational strategies to challenge PbP 2a with series of fifty-five 'ala-ala' and 'ala-pro' sulphonamide-dipeptides. Binding stability of two compounds (labeled: 10i and 10n) with theoretical Ki in nM and µM ranges, for PbP 2a active and allosteric sites respectively, were investigated using molecular dynamics simulations. In addition, the results of the sensitivity of four strains of MRSA for compounds 10i and 10n obtained revealed the compounds at 10 µg/ml caused two isolates (S4 and S10) to revert to being susceptible. Finally, a reliable binding conformations of both compounds in the two binding sites of PbP 2a are described to provide rationale for structure-activity optimization of this series.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Akachukwu Ibezim
- Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka, Nigeria.,Department of Biotechnology, Vellore Institute of Technology, Vellore, Tamilnadu, India
| | - Raphael Onuku
- Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka, Nigeria
| | - Chidalu Ottih
- Department of Microbiology, University of Nigeria, Nsukka, Nigeria
| | - Ifeoma Ezeonu
- Department of Microbiology, University of Nigeria, Nsukka, Nigeria
| | - Efeturi Onoabedje
- Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria
| | | | - Ngozi Nwodo
- Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka, Nigeria
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23
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Li QQ, Chae HS, Kang OH, Kwon DY. Synergistic Antibacterial Activity with Conventional Antibiotics and Mechanism of Action of Shikonin against Methicillin-Resistant Staphylococcus aureus. Int J Mol Sci 2022; 23:ijms23147551. [PMID: 35886892 PMCID: PMC9322759 DOI: 10.3390/ijms23147551] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 12/11/2022] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a troublesome pathogen that poses a global threat to public health. Shikonin (SKN) isolated from Lithospermum erythrorhizon (L. erythrorhizon) possesses a variety of biological activities. This study aims to explore the effect of the combined application of SKN and traditional antibiotics on the vitality of MRSA and the inherent antibacterial mechanism of SKN. The synergies between SKN and antibiotics against MRSA and its clinical strain have been demonstrated by the checkerboard assay and the time-kill assay. The effect of SKN on disrupting the integrity and permeability of bacterial cell membranes was verified by a nucleotide and protein leakage assay and a bacteriolysis assay. As determined by crystal violet staining, SKN inhibited the biofilm formation of clinical MRSA strains. The results of Western blot and qRT-PCR showed that SKN could inhibit the expression of proteins and genes related to drug resistance and S. aureus exotoxins. SKN inhibited the ability of RAW264.7 cells to release the pro-inflammatory cytokines TNF-α and IL-6, as measured by ELISA. Our findings suggest that SKN has the potential to be developed as a promising alternative for the treatment of MRSA infections.
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Affiliation(s)
- Qian-Qian Li
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Iksan 54538, Jeonbuk, Korea;
| | - Hee-Sung Chae
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA;
| | - Ok-Hwa Kang
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Iksan 54538, Jeonbuk, Korea;
- Correspondence: (O.-H.K.); (D.-Y.K.); Tel.: +82-63-850-6802 (O.-H.K.)
| | - Dong-Yeul Kwon
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Iksan 54538, Jeonbuk, Korea;
- Correspondence: (O.-H.K.); (D.-Y.K.); Tel.: +82-63-850-6802 (O.-H.K.)
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24
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Ibarra-Hernández JA, Gómez-Balderas R, Nivón-Ramírez D, García-Estrada JG, Mendoza-Jiménez DA, Martínez-Zaldívar A, Cruz-Sánchez TA, Tovar-Betancourt N, Luna-Mora RA, Penieres-Carrillo JG. Novel Compounds Based on Chalcone- and Pyrazoline-DIM Hybrids as Inhibitors of Staphylococcus aureus, Synthesis, DFT Studies, Biological Evaluation and Docking Studies. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2021.131499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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25
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Abeydeera N, Yu B, Pant BD, Kim MH, Huang SD. Harnessing the toxicity of dysregulated iron uptake for killing Staphylococcus aureus: reality or mirage? Biomater Sci 2022; 10:474-484. [PMID: 34904144 PMCID: PMC8860634 DOI: 10.1039/d1bm01743h] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Iron is essential for all forms of life including pathogenic bacteria. However, iron is also a double-edged sword in biology, as increase of iron uptake can result in reactive oxygen species (ROS)-triggered cell death from the iron-catalyzed Fenton reaction. In this study, we demonstrate that iron-hinokitiol, Fe(hinok)3, a neutral Fe(III) complex formed with the naturally occurring metal chelator hinokitiol; (2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one) can harness the clear ability, due to its high lipophilicity and the nonpolar nature, to penetrate the cell membrane of Staphylococcus aureus (SA) and exhibit potent antimicrobial activity that is enhanced by approximately 10 000 times as compared with hinokitiol itself. Additionally, this Fe(III) complex shows a strong ability to inhibit biofilm formation. More importantly, the development of resistance in SA toward this complex is considerably hampered in comparison with that toward ciprofloxacin. The in vivo evaluation of antimicrobial efficacy in the murine model of skin wound infection by SA confirms that the treatment with a single dose of this complex can reduce the bacterial burden by 83%, demonstrating the therapeutic potential of Fe(hinok)3 in treating skin and soft tissue infections.
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Affiliation(s)
- Nalin Abeydeera
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44240, USA.
| | - Bing Yu
- Department of Biological Sciences, Kent State University, Kent, OH 44240, USA
| | - Bishnu D Pant
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44240, USA.
| | - Min-Ho Kim
- Department of Biological Sciences, Kent State University, Kent, OH 44240, USA
| | - Songping D Huang
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44240, USA.
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26
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Megahed SH, Rasheed S, Herrmann J, El-Hossary EM, El-Shabrawy YI, Abadi AH, Engel M, Müller R, Abdel-Halim M, Hamed MM. Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Modification of the benzenoid part. Bioorg Med Chem Lett 2022; 59:128531. [PMID: 35007723 DOI: 10.1016/j.bmcl.2022.128531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/21/2021] [Accepted: 01/04/2022] [Indexed: 11/19/2022]
Abstract
Bacterial resistance to currently used antibiotics demands the development of novel antibacterial agents with good safety margins and sufficient efficacy against multi-drug resistant isolates. We have previously described the synthesis of N-butyl-2-(butylthio)quinazolin-4-amine (I) as an optimized hit with broad-spectrum antibacterial activity and low cytotoxicity. In addition, we have identified a potential growing vector for this series of compounds. Herein, we describe further hit optimization which includes systematic diversifications of both the benzenoid part and the substituents at position 6 and 7 of compound I. Growing of the molecule beside the core modifications yielded several compounds with remarkable anti(myco)bacterial activity against a panel of pathogenic bacteria, including drug-resistant strains. Compound 12 showed a 2-4 fold improvement in activity than I against S. aureus Newman, S. pneumoniae DSM-20566 and E. faecalis DSM-20478. The compounds also showed a good safety profile towards human HepG2 cells.
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Affiliation(s)
- Sarah H Megahed
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt
| | - Sari Rasheed
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
| | - Jennifer Herrmann
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
| | - Ebaa M El-Hossary
- Drug Radiation Research Department, National Centre for Radiation Research and Technology, Egyptian Atomic Energy Authority, Ahmed El-Zomor St. 3, El-Zohoor Dist., Nasr City, 11765 Cairo, Egypt
| | - Yahia I El-Shabrawy
- Department of Microbiology and Immunology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt
| | - Ashraf H Abadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt
| | - Matthias Engel
- Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany
| | - Rolf Müller
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany; Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt.
| | - Mostafa M Hamed
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany.
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27
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Zhang PL, Gopala L, Zhang SL, Cai GX, Zhou CH. An unanticipated discovery towards novel naphthalimide corbelled aminothiazoximes as potential anti-MRSA agents and allosteric modulators for PBP2a. Eur J Med Chem 2021; 229:114050. [PMID: 34922190 DOI: 10.1016/j.ejmech.2021.114050] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/26/2021] [Accepted: 12/09/2021] [Indexed: 12/14/2022]
Abstract
Available therapeutic strategies are urgently needed to conquer multidrug resistance of MRSA. A visible effort was guided towards the advancement of novel antibacterial framework of naphthalimide corbelled aminothiazoximes, and desired to assert some insight on the conjunction of individual pharmacophore with distinct biological activities and unique action mechanism. Preliminary assessment displayed that dimethylenediamine derivative 13d presented a wonderful inhibition on MRSA (MIC = 0.5 μg/mL), and showed excellent membrane selectivity (HC50 > 200 μg/mL) from an electrostatic distinction of the electronegative bacterial membranes and the electroneutral mammalian membranes. Moreover, 13d could effectually relieve the development of MRSA resistance. Investigations into explaining the mechanism of anti-MRSA disclosed that 13d displayed strong lipase affinity, which facilitated its permeation into cell membrane, causing membrane depolarization, leakage of cytoplasmic contents and lactate dehydrogenase (LDH) inhibition. Meanwhile, 13d could exert interaction with DNA to hinder biological function of DNA, and disrupt the antioxidant defense system of MRSA through up-regulation of ROS subjected the strain to oxidative stress. In particular, the unanticipated mechanism for naphthalimide corbelled aminothiazoximes that 13d could suppress the expression of PBP2a by inducing allosteric modulation of PBP2a and triggering the open of the active site, was discovered for the first time. These findings of naphthalimide corbelled aminothiazoximes as a small-molecule class of anti-MRSA agents held promise in strategies for treatment of MRSA infections.
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Affiliation(s)
- Peng-Li Zhang
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China
| | - Lavanya Gopala
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China
| | - Shao-Lin Zhang
- School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, China.
| | - Gui-Xin Cai
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
| | - Cheng-He Zhou
- Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
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28
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Marzullo P, Vasto S, Buscemi S, Pace A, Nuzzo D, Palumbo Piccionello A. Ammonium Formate-Pd/C as a New Reducing System for 1,2,4-Oxadiazoles. Synthesis of Guanidine Derivatives and Reductive Rearrangement to Quinazolin-4-Ones with Potential Anti-Diabetic Activity. Int J Mol Sci 2021; 22:12301. [PMID: 34830187 PMCID: PMC8621334 DOI: 10.3390/ijms222212301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/10/2021] [Accepted: 11/10/2021] [Indexed: 11/17/2022] Open
Abstract
1,2,4-Oxadiazole is a heterocycle with wide reactivity and many useful applications. The reactive O-N bond is usually reduced using molecular hydrogen to obtain amidine derivatives. NH4CO2H-Pd/C is here demonstrated as a new system for the O-N reduction, allowing us to obtain differently substituted acylamidine, acylguanidine and diacylguanidine derivatives. The proposed system is also effective for the achievement of a reductive rearrangement of 5-(2'-aminophenyl)-1,2,4-oxadiazoles into 1-alkylquinazolin-4(1H)-ones. The alkaloid glycosine was also obtained with this method. The obtained compounds were preliminarily tested for their biological activity in terms of their cytotoxicity, induced oxidative stress, α-glucosidase and DPP4 inhibition, showing potential application as anti-diabetics.
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Affiliation(s)
- Paola Marzullo
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche-STEBICEF, Università degli Studi di Palermo, 90128 Palermo, Italy; (P.M.); (S.B.); (A.P.); (D.N.)
| | - Sonya Vasto
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche-STEBICEF, Università degli Studi di Palermo, 90128 Palermo, Italy; (P.M.); (S.B.); (A.P.); (D.N.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Silvestre Buscemi
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche-STEBICEF, Università degli Studi di Palermo, 90128 Palermo, Italy; (P.M.); (S.B.); (A.P.); (D.N.)
| | - Andrea Pace
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche-STEBICEF, Università degli Studi di Palermo, 90128 Palermo, Italy; (P.M.); (S.B.); (A.P.); (D.N.)
| | - Domenico Nuzzo
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche-STEBICEF, Università degli Studi di Palermo, 90128 Palermo, Italy; (P.M.); (S.B.); (A.P.); (D.N.)
- Consiglio Nazionale delle Ricerche, Istituto di Biofisica (CNR-IBF), 90146 Palermo, Italy
| | - Antonio Palumbo Piccionello
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche-STEBICEF, Università degli Studi di Palermo, 90128 Palermo, Italy; (P.M.); (S.B.); (A.P.); (D.N.)
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29
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Aboushady D, Rasheed SS, Herrmann J, Maher A, El-Hossary EM, Ibrahim ES, Abadi AH, Engel M, Müller R, Abdel-Halim M, Hamed MM. Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Optimization of the 2,4-substituents. Bioorg Chem 2021; 117:105422. [PMID: 34700110 DOI: 10.1016/j.bioorg.2021.105422] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/20/2021] [Accepted: 10/08/2021] [Indexed: 12/14/2022]
Abstract
The emergence of bacterial resistance has triggered a multitude of efforts to develop new antibacterial agents. There are many compounds in literature that were reported as potent antibacterial agents, however, they lacked the required safety to mammalian cells or no clear picture about their toxicity profile was presented. Inspired by discovered hit from our in-house library and by previously reported 2,4-diaminosubstituted quinazolines, we describe the design and synthesis of novel 2,4-disubstituted-thioquinazolines (3-13 and 36), 2-thio-4-amino substituted quinazolines (14-33) and 6-substituted 2,4-diamonsubstituted quinazolines (37-39). The synthesized compounds showed potent antibacterial activity against a panel of Gram-positive, efflux deficient E.coli and Mycobacterium smegmatis. The panel also involved resistant strains including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium, in addition to Mycobacterium smegmatis. The newly synthesized compounds revealed MIC values against the tested strains ranging from 1 to 64 µg/mL with a good safety profile. Most of the 2-thio-4-amino substituted-quinazolines showed significant antimycobacterial activity with the variations at position 2 and 4 offering additional antibacterial activity against the different strains. Compared to previously reported 2,4-diaminosubstituted quinazolines, the bioisosteric replacement of the 2-amino with sulfur offered a successful approach to keep the high antibacterial potency while substantially improving safety profile as indicated by the reduced activity on different cell lines and a lack of hemolytic activity.
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Affiliation(s)
- Dina Aboushady
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt
| | - Sari S Rasheed
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
| | - Jennifer Herrmann
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
| | - Ahmed Maher
- Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), 6(th) of October City, Egypt; Department of Biology and Biochemistry, School of Life and Medical Sciences, University of Hertfordshire hosted by Global Academic Foundation, Cairo, Egypt
| | - Ebaa M El-Hossary
- Drug Radiation Research Department, National Centre for Radiation Research and Technology, Egyptian Atomic Energy Authority, Ahmed El-Zomor St. 3, El-Zohoor Dist., 11765 Cairo, Egypt
| | - Eslam S Ibrahim
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt; Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Strasse 2/Bau D15, 97080 Würzburg, Germany
| | - Ashraf H Abadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt
| | - Matthias Engel
- Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany
| | - Rolf Müller
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany; Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt.
| | - Mostafa M Hamed
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany.
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30
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Wang XX, Ma CT, Jiang YX, Ge YJ, Liu FY, Xu WG. Cefoperazone sodium/sulbactam sodium vs piperacillin sodium/tazobactam sodium for treatment of respiratory tract infection in elderly patients. World J Clin Cases 2021; 9:8694-8701. [PMID: 34734047 PMCID: PMC8546814 DOI: 10.12998/wjcc.v9.i29.8694] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/05/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Respiratory tract infections in the elderly are difficult to cure and can easily recur, thereby posing a great threat to patient prognosis and quality of life.
AIM To investigate the therapeutic effects of different antibiotics in elderly patients with respiratory tract infection.
METHODS Seventy-four elderly patients with respiratory tract infection were randomly allocated to a study (n = 37; treated with cefoperazone sodium/sulbactam sodium) or control (n = 37; treated with piperacillin sodium/tazobactam sodium on the basis of routine symptomatic support) group. Both groups were treated for 7 d. Time to symptom relief (leukocyte recovery; body temperature recovery; cough and sputum disappearance; and rale disappearance time), treatment effect, and laboratory indexes [procalcitonin (PCT), C-reactive protein (CRP), white blood cell count (WBC), and neutrophil percentage (NE)] before and 7 d after treatment and the incidence of adverse reactions were assessed.
RESULTS In the study group, the time to WBC normalization (6.79 ± 2.09 d), time to body temperature normalization (4.15 ± 1.08 d), time to disappearance of cough and sputum (6.19 ± 1.56 d), and time to disappearance of rales (6.68 ± 1.43 d) were shorter than those of the control group (8.89 ± 2.32 d, 5.81 ± 1.33 d, 8.77 ± 2.11 d, and 8.69 ± 2.12 d, respectively; P = 0.000). Total effective rate was higher in the study group (94.59% vs 75.68%, P = 0.022). Serum PCT (12.89 ± 3.96 μg/L), CRP (19.62 ± 6.44 mg/L), WBC (20.61 ± 6.38 × 109/L), and NE (86.14 ± 7.21%) levels of the study group before treatment were similar to those of the control group (14.05 ± 4.11 μg/L, 18.79 ± 5.96 mg/L, 21.21 ± 5.59 × 109/L, and 84.39 ± 6.95%, respectively) with no significant differences (P = 0.220, 0.567, 0.668, and 0.291, respectively). After 7 d of treatment, serum PCT, CRP, WBC, and NE levels in the two groups were lower than those before treatment. Serum PCT (2.01 ± 0.56 μg/L), CRP (3.11 ± 1.02 mg/L), WBC (5.10 ± 1.83 × 109/L), and NE (56.35 ± 7.17%) levels were lower in the study group than in the control group (3.29 ± 0.64 μg/L, 5.67 ± 1.23 mg/L, 8.13 ± 3.01 × 109/L, and 64.22 ± 8.08%, respectively; P = 0.000). There was no significant difference in the incidence of adverse reactions between the groups (7.50% vs 12.50%, P = 0.708).
CONCLUSION Piperacillin sodium/tazobactam sodium is superior to cefoperazone sodium/ sulbactam sodium in the treatment of elderly patients with respiratory tract infection with a similar safety profile.
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Affiliation(s)
- Xiao-Xia Wang
- Department of Cadre Health, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
| | - Cheng-Tai Ma
- Department of Emergency Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266011, Shandong Province, China
| | - Yan-Xia Jiang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266011, Shandong Province, China
| | - Yun-Jie Ge
- Department of Cadre Health, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
| | - Fa-Yun Liu
- Department of Pulmonary, Shandong Qingdao Hospital of Integrated Traditional Chinese and Western Medicine, Qingdao 266011, Shandong Province, China
| | - Wen-Gang Xu
- Department of Pulmonary, Shandong Qingdao Hospital of Integrated Traditional Chinese and Western Medicine, Qingdao 266011, Shandong Province, China
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31
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Samotrueva MA, Ozerov AA, Starikova AA, Gabitova NM, Merezhkina DV, Tsibizova AA, Tyurenkov IN. ANTIMICROBIAL ACTIVITY STUDY OF NEW QUINAZOLIN-4(3H)-ONES AGAINST STAPHYLOCOCCUS AUREUS AND STREPTOCOCCUS PNEUMONIAE. PHARMACY & PHARMACOLOGY 2021. [DOI: 10.19163/2307-9266-2021-9-4-318-329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Quinazolin-4(3H)-one derivatives exhibiting a wide spectrum of a pharmacological activity, represent a promising class of substances used to obtain antibacterial agents, which is especially important in the context of the emergence of pathogenic microorganisms’ resistance to drugs used in medicine. It has been proved that compounds having a naphthyl radical in the molecule, as well as an amide group bound to the benzene ring as quinazolinone substituents, are characterized by a pronounced antimicrobial activity against Staphylococcus aureus and Streptococcus pneumoniae.The aim of the research is a primary microbiological screening of the in vitro antimicrobial activity of new quinazolin-4(3H)-one derivatives against Staphylococcus aureus and Streptococcus pneumoniae, as well as the assessment of the relationship between the pharmacological effect and the structural transformation of the substance molecule, lipophilicity and the possibility of forming resistance to them.Materials and methods. The experimental studies have been carried out using well-known nosocomial pathogens of infectious and inflammatory diseases Staphylococcus aureus and Streptococcus pneumoniae by a serial dilution method.Results. A compound containing a naphthyl radical in its structure, which contributes to an increase in the hydrophobicity of the substance and its solubility in the membrane of a bacterial cell, has a bacteriostatic effect against both Staphylococcus aureus and Streptococcus pneumoniae. A similar pharmacological effect is exhibited by a derivative with an amide group as a substituent of the quinazolinone nucleus linked to a phenyl radical, which probably contributes to an increase in the degree of binding to active sites of enzymes involved in the DNA replication, and protein synthesis. Obviously, the increased lipophilicity, which promotes better binding to the efflux protein, cannot serve as objective characteristics of the emergence possibility of the pathogen’s resistance to this substance.Conclusion. Among the synthesized compounds, the leading substances that exhibit an antimicrobial activity against Staphylococcus aureus and Streptococcus pneumonia, have been identified. The assessment of the chemical structure made it possible to substantiate their pharmacological action and draw conclusions about the possibility of developing resistance to it in microbial cells.
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Affiliation(s)
- M. A. Samotrueva
- Аstrakhan State Medical University
121, Bakinskaya Str., Astrakhan, Russia, 414000
| | - A. A. Ozerov
- 1. Volgograd State Medical University
1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131
2. Volgograd Medical Research Center
1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131
| | - A. A. Starikova
- Аstrakhan State Medical University
121, Bakinskaya Str., Astrakhan, Russia, 414000
| | - N. M. Gabitova
- 1. Аstrakhan State Medical University
121, Bakinskaya Str., Astrakhan, Russia, 414000
2. Scientific Research Institute for the Study of Leprosy
3, Nikolay Ostrovsky Ave., Astrakhan, Russia, 414057
| | - D. V. Merezhkina
- Volgograd State Medical University
1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131
| | - A. A. Tsibizova
- Аstrakhan State Medical University
121, Bakinskaya Str., Astrakhan, Russia, 414000
| | - I. N. Tyurenkov
- 1. Volgograd State Medical University
1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131
2. Volgograd Medical Research Center
1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131
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Gunasekharan M, Choi TI, Rukayadi Y, Mohammad Latif MA, Karunakaran T, Mohd Faudzi SM, Kim CH. Preliminary Insight of Pyrrolylated-Chalcones as New Anti-Methicillin-Resistant Staphylococcus aureus (Anti-MRSA) Agents. Molecules 2021; 26:molecules26175314. [PMID: 34500755 PMCID: PMC8434082 DOI: 10.3390/molecules26175314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 11/16/2022] Open
Abstract
Bacterial infections are regarded as one of the leading causes of fatal morbidity and death in patients infected with diseases. The ability of microorganisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), to develop resistance to current drugs has evoked the need for a continuous search for new drugs with better efficacies. Hence, a series of non-PAINS associated pyrrolylated-chalcones (1–15) were synthesized and evaluated for their potency against MRSA. The hydroxyl-containing compounds (8, 9, and 10) showed the most significant anti-MRSA efficiency, with the MIC and MBC values ranging from 0.08 to 0.70 mg/mL and 0.16 to 1.88 mg/mL, respectively. The time-kill curve and SEM analyses exhibited bacterial cell death within four hours after exposure to 9, suggesting its bactericidal properties. Furthermore, the docking simulation between 9 and penicillin-binding protein 2a (PBP2a, PDB ID: 6Q9N) suggests a relatively similar bonding interaction to the standard drug with a binding affinity score of −7.0 kcal/mol. Moreover, the zebrafish model showed no toxic effects in the normal embryonic development, blood vessel formation, and apoptosis when exposed to up to 40 µM of compound 9. The overall results suggest that the pyrrolylated-chalcones may be considered as a potential inhibitor in the design of new anti-MRSA agents.
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Affiliation(s)
- Mohanapriya Gunasekharan
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | - Tae-Ik Choi
- Department of Biology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea;
| | - Yaya Rukayadi
- Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Muhammad Alif Mohammad Latif
- Centre of Foundation Studies for Agricultural Science, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | | | - Siti Munirah Mohd Faudzi
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
- Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
- Correspondence: (S.M.M.F.); (C.-H.K.)
| | - Cheol-Hee Kim
- Department of Biology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea;
- Correspondence: (S.M.M.F.); (C.-H.K.)
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Gallique M, Wei K, Maisuria VB, Okshevsky M, McKay G, Nguyen D, Tufenkji N. Cranberry-Derived Proanthocyanidins Potentiate β-Lactam Antibiotics against Resistant Bacteria. Appl Environ Microbiol 2021; 87:e00127-21. [PMID: 33712420 PMCID: PMC8117774 DOI: 10.1128/aem.00127-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
The emergence and spread of extended-spectrum β-lactamases (ESBLs), metallo-β-lactamases (MBLs), or variant low-affinity penicillin-binding proteins (PBPs) pose a major threat to our ability to treat bacterial infection using β-lactam antibiotics. Although combinations of β-lactamase inhibitors with β-lactam agents have been clinically successful, there are no MBL inhibitors in current therapeutic use. Furthermore, recent clinical use of new-generation cephalosporins targeting PBP2a, an altered PBP, has led to the emergence of resistance to these antimicrobial agents. Previous work shows that natural polyphenols such as cranberry-extracted proanthocyanidins (cPAC) can potentiate non-β-lactam antibiotics against Gram-negative bacteria. This study extends beyond previous work by investigating the in vitro effect of cPAC in overcoming ESBL-, MBL-, and PBP2a-mediated β-lactam resistance. The results show that cPAC exhibit variable potentiation of different β-lactams against β-lactam-resistant Enterobacteriaceae clinical isolates as well as ESBL- and MBL-producing E. coli We also discovered that cPAC have broad-spectrum inhibitory properties in vitro on the activity of different classes of β-lactamases, including CTX-M3 ESBL and IMP-1 MBL. Furthermore, we observe that cPAC selectively potentiate oxacillin and carbenicillin against methicillin-resistant but not methicillin-sensitive staphylococci, suggesting that cPAC also interfere with PBP2a-mediated resistance. This study motivates the need for future work to identify the most bioactive compounds in cPAC and to evaluate their antibiotic-potentiating efficacy in vivoIMPORTANCE The emergence of β-lactam-resistant Enterobacteriaceae and staphylococci compromises the effectiveness of β-lactam-based therapy. By acquisition of ESBLs, MBLs, or PBPs, it is highly likely that bacteria may become completely resistant to the most effective β-lactam agents in the near future. In this study, we described a natural extract rich in proanthocyanidins which exerts adjuvant properties by interfering with two different resistance mechanisms. By their broad-spectrum inhibitory ability, cranberry-extracted proanthocyanidins could have the potential to enhance the effectiveness of existing β-lactam agents.
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Affiliation(s)
- Mathias Gallique
- Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Kuan Wei
- Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Vimal B Maisuria
- Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada
| | - Mira Okshevsky
- Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada
| | - Geoffrey McKay
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Dao Nguyen
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Nathalie Tufenkji
- Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada
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34
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Synthesis and Biological Evaluation of Quinazolonethiazoles as New Potential Conquerors towards
Pseudomonas Aeruginosa. CHINESE J CHEM 2021. [DOI: 10.1002/cjoc.202000627] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Fisher JF, Mobashery S. β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium. Chem Rev 2021; 121:3412-3463. [PMID: 33373523 PMCID: PMC8653850 DOI: 10.1021/acs.chemrev.0c01010] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The biological diversity of the unicellular bacteria-whether assessed by shape, food, metabolism, or ecological niche-surely rivals (if not exceeds) that of the multicellular eukaryotes. The relationship between bacteria whose ecological niche is the eukaryote, and the eukaryote, is often symbiosis or stasis. Some bacteria, however, seek advantage in this relationship. One of the most successful-to the disadvantage of the eukaryote-is the small (less than 1 μm diameter) and nearly spherical Staphylococcus aureus bacterium. For decades, successful clinical control of its infection has been accomplished using β-lactam antibiotics such as the penicillins and the cephalosporins. Over these same decades S. aureus has perfected resistance mechanisms against these antibiotics, which are then countered by new generations of β-lactam structure. This review addresses the current breadth of biochemical and microbiological efforts to preserve the future of the β-lactam antibiotics through a better understanding of how S. aureus protects the enzyme targets of the β-lactams, the penicillin-binding proteins. The penicillin-binding proteins are essential enzyme catalysts for the biosynthesis of the cell wall, and understanding how this cell wall is integrated into the protective cell envelope of the bacterium may identify new antibacterials and new adjuvants that preserve the efficacy of the β-lactams.
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Affiliation(s)
- Jed F Fisher
- Department of Chemistry and Biochemistry, McCourtney Hall, University of Notre Dame, Notre Dame Indiana 46556, United States
| | - Shahriar Mobashery
- Department of Chemistry and Biochemistry, McCourtney Hall, University of Notre Dame, Notre Dame Indiana 46556, United States
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Chang M, Mahasenan KV, Hermoso JA, Mobashery S. Unconventional Antibacterials and Adjuvants. Acc Chem Res 2021; 54:917-929. [PMID: 33512995 DOI: 10.1021/acs.accounts.0c00776] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The need for new classes of antibacterials is genuine in light of the dearth of clinical options for the treatment of bacterial infections. The prodigious discoveries of antibiotics during the 1940s to 1970s, a period wistfully referred to as the Golden Age of Antibiotics, have not kept up in the face of emergence of resistant bacteria in the past few decades. There has been a renewed interest in old drugs, the repurposing of the existing antibiotics and pairing of synergistic antibiotics or of an antibiotic with an adjuvant. Notwithstanding, discoveries of novel classes of these life-saving drugs have become increasingly difficult, calling for new paradigms. We describe, herein, three strategies from our laboratories toward discoveries of new antibacterials and adjuvants using computational and multidisciplinary experimental methods. One approach targets penicillin-binding proteins (PBPs), biosynthetic enzymes of cell-wall peptidoglycan, for discoveries of non-β-lactam inhibitors. Oxadiazoles and quinazolinones emerged as two structural classes out of these efforts. Several hundred analogs of these two classes of antibiotics have been synthesized and fully characterized in our laboratories. A second approach ventures into inhibition of allosteric regulation of cell-wall biosynthesis. The mechanistic details of allosteric regulation of PBP2a of Staphylococcus aureus, discovered in our laboratories, is outlined. The allosteric site in this protein is at 60 Å distance to the active site, whereby ligand binding at the former makes access to the latter by the substrate possible. We have documented that both quinazolinones and ceftaroline, a fifth-generation cephalosporin, bind to the allosteric site in manifestation of the antibacterial activity. Attempts at inhibition of the regulatory phosphorylation events identified three classes of antibacterial adjuvants and one class of antibacterials, the picolinamides. The chemical structures for these hits went through diversification by synthesis of hundreds of analogs. These analogs were characterized in various assays for identification of leads with adjuvant and antibacterial activities. Furthermore, we revisited the mechanism of bulgecins, a class of adjuvants discovered and abandoned in the 1980s. These compounds potentiate the activities of β-lactam antibiotics by the formation of bulges at the sites of septum formation during bacterial replication, which are points of structural weakness in the envelope. These bulges experience rupture, which leads to bacterial death. Bulgecin A inhibits the lytic transglycosylase Slt of Pseudomonas aeruginosa as a likely transition-state mimetic for its turnover of the cell-wall peptidoglycan. Once damage to cell wall is inflicted by a β-lactam antibiotic, the function of Slt is to repair the damage. When Slt is inhibited by bulgecin A, the organism cannot cope with it and would undergo rapid lysis. Bulgecin A is an effective adjuvant of β-lactam antibiotics. These discoveries of small-molecule classes of antibacterials or of adjuvants to antibacterials hold promise in strategies for treatment of bacterial infections.
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Affiliation(s)
- Mayland Chang
- Department of Chemistry and Biochemistry, University of Notre Dame, McCourtney Hall, Notre Dame Indiana 46556, United States
| | - Kiran V. Mahasenan
- Department of Chemistry and Biochemistry, University of Notre Dame, McCourtney Hall, Notre Dame Indiana 46556, United States
| | - Juan A. Hermoso
- Departamento de Cristalografía y Biología Estructural, Instituto de Química-Física “Rocasolano”, CSIC, Serrano 119, 28006-Madrid Spain
| | - Shahriar Mobashery
- Department of Chemistry and Biochemistry, University of Notre Dame, McCourtney Hall, Notre Dame Indiana 46556, United States
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Li QQ, Luo J, Liu XQ, Kwon DY, Kang OH. Eleutheroside K isolated from Acanthopanax henryi (Oliv.) Harms suppresses methicillin resistance of Staphylococcus aureus. Lett Appl Microbiol 2020; 72:669-676. [PMID: 32955753 DOI: 10.1111/lam.13389] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/03/2020] [Accepted: 09/10/2020] [Indexed: 01/03/2023]
Abstract
Acanthopanax (A.) henryi (Oliv.) Harms contain many bioactive compounds commonly used in traditional Chinese medicine. The objective of the present study was to investigate the antibacterial activity of the single constituent, Eleutheroside K (ETSK) isolated from the leaves of A. henryi (Oliv.) Harms, against methicillin-resistant Staphylococcus (S.) aureus (MRSA). Broth microdilution assay was used to measure the minimal inhibitory concentration (MIC) and the MIC values of ETSK against eight clinical S. aureus strains were all 50 µg ml-1 . At sub-inhibitory concentrations, a synergistic effect between oxacillin (OXA) and ETSK was confirmed using checkerboard dilution assay and time-kill curve analysis. The bacteriostatic effect became more pronounced when ETSK was used in combination with detergent (Triton X-100) or ATPase inhibitor (N, N'-dicyclohexylcarbodiimide). According to western blot analysis, the down-regulated expression of Penicillin-binding protein 2a (PBP2a) further validated that the bacterial activity was inhibited when treated with ETSK in a dose-dependent manner. Results based on our study verified that ETSK significantly suppressed MRSA infections and emphasized the potential application of ETSK as a novel anti-MRSA natural drug.
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Affiliation(s)
- Q-Q Li
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Jeonbuk, Korea
| | - J Luo
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, P.R. China
| | - X-Q Liu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, P.R. China
| | - D-Y Kwon
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Jeonbuk, Korea
| | - O-H Kang
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Jeonbuk, Korea
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38
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Song R, Yu B, Friedrich D, Li J, Shen H, Krautscheid H, Huang SD, Kim MH. Naphthoquinone-derivative as a synthetic compound to overcome the antibiotic resistance of methicillin-resistant S. aureus. Commun Biol 2020; 3:529. [PMID: 32973345 PMCID: PMC7518446 DOI: 10.1038/s42003-020-01261-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/25/2020] [Indexed: 12/15/2022] Open
Abstract
The treatment of Staphylococcus aureus (S. aureus) infections has become more difficult due to the emergence of multidrug resistance in the bacteria. Here, we report the synthesis of a lawsone (2-hydroxy-1,4-naphthoquinone)-based compound as an antimicrobial agent against methicillin-resistant S. aureus (MRSA). A series of lawsone-derivative compounds were synthesized by means of tuning the lipophilicity of lawsone and screened for minimum inhibitory concentrations against MRSA to identify a candidate compound that possesses a potent antibacterial activity. The identified lawsone-derivative compound exhibited significantly improved drug resistance profiles against MRSA compared to conventional antibiotics. The therapeutic efficacy of the compound was validated using murine models of wound infection as well as non-lethal systemic infection induced by MRSA. Our study further revealed the multifaceted modes of action of the compound, mediated by three distinctive mechanisms: (1) cell membrane damage, (2) chelation of intracellular iron ions, and (3) generation of intracellular reactive oxygen species. Ronghui Song et al. demonstrate that a lawsone (2-hydroxy-1,4-naphthoquinone)-based compound decreases the drug resistance of methicillin-resistant Staphylococcus aureus much better than conventional antibiotics. This study provides insights into the design and action mechanism of effective antibiotics that overcome the antibiotic resistance of bacteria.
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Affiliation(s)
- Ronghui Song
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH, 44240, USA
| | - Bing Yu
- Department of Biological Sciences, Kent State University, Kent, OH, 44240, USA
| | - Dirk Friedrich
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH, 44240, USA
| | - Junfeng Li
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH, 44240, USA
| | - Hao Shen
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH, 44240, USA
| | - Harald Krautscheid
- Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, 04103, Leipzig, Germany
| | - Songping D Huang
- Department of Chemistry and Biochemistry, Kent State University, Kent, OH, 44240, USA.
| | - Min-Ho Kim
- Department of Biological Sciences, Kent State University, Kent, OH, 44240, USA.
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39
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Prasher P, Sharma M, Aljabali AAA, Gupta G, Negi P, Kapoor DN, Singh I, Zacconi FC, Jesus Andreoli Pinto T, Silva MW, Bakshi HA, Chellappan DK, Tambuwala MM, Dua K. Hybrid molecules based on 1,3,5‐triazine as potential therapeutics: A focused review. Drug Dev Res 2020; 81:837-858. [DOI: 10.1002/ddr.21704] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/25/2020] [Accepted: 05/29/2020] [Indexed: 12/30/2022]
Affiliation(s)
- Parteek Prasher
- UGC‐Sponsored Centre for Advanced Studies, Department of Chemistry Guru Nanak Dev University Amritsar India
- Department of Chemistry University of Petroleum & Energy Studies Dehradun India
| | - Mousmee Sharma
- UGC‐Sponsored Centre for Advanced Studies, Department of Chemistry Guru Nanak Dev University Amritsar India
- Department of Chemistry Uttaranchal University Dehradun India
| | - Alaa A. A. Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology Faculty of Pharmacy, Yarmouk University Irbid Jordan
| | - Gaurav Gupta
- School of Pharmacy Suresh Gyan Vihar University Jaipur India
| | - Poonam Negi
- School of Pharmaceutical Sciences Shoolini University of Biotechnology and Management Sciences Solan India
| | - Deepak N. Kapoor
- School of Pharmaceutical Sciences Shoolini University of Biotechnology and Management Sciences Solan India
| | - Inderbir Singh
- Chitkara College of Pharmacy Chitkara University Punjab India
| | - Flavia C. Zacconi
- Departamento de Organica, faculdad de Quimica y de Farmacia, Pontificia Universidad Catolica de Chile Santiago Chile
| | | | - Mateus Webba Silva
- School of Pharmacy and Pharmaceutical Science Ulster University Coleraine United Kingdom
| | - Hamid A. Bakshi
- School of Pharmacy and Pharmaceutical Science Ulster University Coleraine United Kingdom
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy International Medical University Kuala Lumpur Malaysia
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Science Ulster University Coleraine United Kingdom
| | - Kamal Dua
- School of Pharmaceutical Sciences Shoolini University of Biotechnology and Management Sciences Solan India
- Discipline of Pharmacy, Graduate School of Health University of Technology Sydney Sydney New South Wales Australia
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) & School of Biomedical Sciences and Pharmacy University of Newcastle Callaghan New South Wales Australia
- Centre for Inflammation, Centenary Institute Royal Prince Alfred Hospital Sydney New South Wales Australia
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40
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Multiple ways to kill bacteria via inhibiting novel cell wall or membrane targets. Future Med Chem 2020; 12:1253-1279. [PMID: 32538147 DOI: 10.4155/fmc-2020-0046] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The rise of antibiotic-resistant infections has been well documented and the need for novel antibiotics cannot be overemphasized. US FDA approved antibiotics target only a small fraction of bacterial cell wall or membrane components, well-validated antimicrobial targets. In this review, we highlight small molecules that inhibit relatively unexplored cell wall and membrane targets. Some of these targets include teichoic acids-related proteins (DltA, LtaS, TarG and TarO), lipid II, Mur family enzymes, components of LPS assembly (MsbA, LptA, LptB and LptD), penicillin-binding protein 2a in methicillin-resistant Staphylococcus aureus, outer membrane protein transport (such as LepB and BamA) and lipoprotein transport components (LspA, LolC, LolD and LolE). Inhibitors of SecA, cell division protein, FtsZ and compounds that kill persister cells via membrane targeting are also covered.
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41
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Johnson ME, Fung LWM. Structural approaches to pathway-specific antimicrobial agents. Transl Res 2020; 220:114-121. [PMID: 32105648 PMCID: PMC7293926 DOI: 10.1016/j.trsl.2020.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/31/2020] [Accepted: 02/03/2020] [Indexed: 10/25/2022]
Abstract
This perspective provides an overview of the evolution of antibiotic discovery from a largely phenotypic-based effort, through an intensive structure-based design focus, to a more holistic approach today. The current focus on antibiotic development incorporates assay and discovery conditions that replicate the host environment as much as feasible. They also incorporate several strategies, including target identification and validation within the whole cell environment, a variety of target deconvolution methods, and continued refinement of structure-based design approaches.
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Affiliation(s)
- Michael E Johnson
- Department of Pharmaceutical Sciences, Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, Illinois.
| | - Leslie W-M Fung
- Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois.
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42
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Qian Y, Allegretta G, Janardhanan J, Peng Z, Mahasenan KV, Lastochkin E, Gozun MMN, Tejera S, Schroeder VA, Wolter WR, Feltzer R, Mobashery S, Chang M. Exploration of the Structural Space in 4(3 H)-Quinazolinone Antibacterials. J Med Chem 2020; 63:5287-5296. [PMID: 32343145 DOI: 10.1021/acs.jmedchem.0c00153] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We report herein the syntheses of 79 derivatives of the 4(3H)-quinazolinones and their structure-activity relationship (SAR) against methicillin-resistant Staphylococcus aureus (MRSA). Twenty one analogs were further evaluated in in vitro assays. Subsequent investigation of the pharmacokinetic properties singled out compound 73 ((E)-3-(5-carboxy-2-fluorophenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one) for further study. The compound synergized with piperacillin-tazobactam (TZP) both in vitro and in vivo in a clinically relevant mouse model of MRSA infection. The TZP combination lacks activity against MRSA, yet it synergized with compound 73 to kill MRSA in a bactericidal manner. The synergy is rationalized by the ability of the quinazolinones to bind to the allosteric site of penicillin-binding protein (PBP)2a, resulting in opening of the active site, whereby the β-lactam antibiotic now is enabled to bind to the active site in its mechanism of action. The combination effectively treats MRSA infection, for which many antibiotics (including TZP) have faced clinical obsolescence.
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Affiliation(s)
- Yuanyuan Qian
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Giuseppe Allegretta
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Jeshina Janardhanan
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Zhihong Peng
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Kiran V Mahasenan
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Elena Lastochkin
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Melissa Malia N Gozun
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Sara Tejera
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Valerie A Schroeder
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - William R Wolter
- Freimann Life Sciences Center, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Rhona Feltzer
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Shahriar Mobashery
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Mayland Chang
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
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43
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Shalaby MAW, Dokla EME, Serya RAT, Abouzid KAM. Penicillin binding protein 2a: An overview and a medicinal chemistry perspective. Eur J Med Chem 2020; 199:112312. [PMID: 32442851 DOI: 10.1016/j.ejmech.2020.112312] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/28/2020] [Accepted: 04/05/2020] [Indexed: 12/17/2022]
Abstract
Antimicrobial resistance is an imminent threat worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the "superbug" family, manifesting resistance through the production of a penicillin binding protein, PBP2a, an enzyme that provides its transpeptidase activity to allow cell wall biosynthesis. PBP2a's low affinity to most β-lactams, confers resistance to MRSA against numerous members of this class of antibiotics. An Achilles' heel of MRSA, PBP2a represents a substantial target to design novel antibiotics to tackle MRSA threat via inhibition of the bacterial cell wall biosynthesis. In this review we bring into focus the PBP2a enzyme and examine the various aspects related to its role in conferring resistance to MRSA strains. Moreover, we discuss several antibiotics and antimicrobial agents designed to target PBP2a and their therapeutic potential to meet such a grave threat. In conclusion, we consider future perspectives for targeting MRSA infections.
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Affiliation(s)
- Menna-Allah W Shalaby
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt
| | - Eman M E Dokla
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt.
| | - Rabah A T Serya
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt
| | - Khaled A M Abouzid
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt.
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Chiang Y, Wong MTY, Essex JW. Molecular Dynamics Simulations of Antibiotic Ceftaroline at the Allosteric Site of Penicillin‐Binding Protein 2a (PBP2a). Isr J Chem 2020. [DOI: 10.1002/ijch.202000012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Ying‐Chih Chiang
- School of ChemistryUniversity of Southampton Southampton SO17 1BJ United Kingdom
| | - Mabel T. Y. Wong
- School of ChemistryUniversity of Southampton Southampton SO17 1BJ United Kingdom
| | - Jonathan W. Essex
- School of ChemistryUniversity of Southampton Southampton SO17 1BJ United Kingdom
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Fisher JF, Mobashery S. Constructing and deconstructing the bacterial cell wall. Protein Sci 2020; 29:629-646. [PMID: 31747090 PMCID: PMC7021008 DOI: 10.1002/pro.3737] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 12/11/2022]
Abstract
The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antibacterial antibiotics disproportionately target bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for bacterial cell-wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre-eminent class of antibiotics-the β-lactams, exemplified by the penicillins and cephalosporins-from the perspective of the evolving mechanisms for bacterial resistance. The mechanism of action of the β-lactams is bacterial cell-wall destruction. In the monoderm (single membrane, Gram-positive staining) pathogen Staphylococcus aureus the dominant resistance mechanism is expression of a β-lactam-unreactive transpeptidase enzyme that functions in cell-wall construction. In the diderm (dual membrane, Gram-negative staining) pathogen Pseudomonas aeruginosa a dominant resistance mechanism (among several) is expression of a hydrolytic enzyme that destroys the critical β-lactam ring of the antibiotic. The key sensing mechanism used by P. aeruginosa is monitoring the molecular difference between cell-wall construction and cell-wall deconstruction. In both bacteria, the resistance pathways are manifested only when the bacteria detect the presence of β-lactams. This review summarizes how the β-lactams are sensed and how the resistance mechanisms are manifested, with the expectation that preventing these processes will be critical to future chemotherapeutic control of multidrug resistant bacteria.
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Affiliation(s)
- Jed F. Fisher
- Department of Chemistry and BiochemistryUniversity of Notre DameSouth BendIndiana
| | - Shahriar Mobashery
- Department of Chemistry and BiochemistryUniversity of Notre DameSouth BendIndiana
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Susceptibility of Methicillin-Resistant Staphylococcus aureus to Five Quinazolinone Antibacterials. Antimicrob Agents Chemother 2019; 64:AAC.01344-19. [PMID: 31611358 PMCID: PMC7187613 DOI: 10.1128/aac.01344-19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 10/08/2019] [Indexed: 11/22/2022] Open
Abstract
The in vitro activities of five quinazolinone antibacterials, compounds Q1 to Q5, were tested against 210 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC50/MIC90 values (in μg/ml) were as follows: Q1, 0.5/2; Q2, 1/4; Q3, 2/4; Q4, 0.06/0.25; and Q5, 0.125/0.5. The in vitro activities of five quinazolinone antibacterials, compounds Q1 to Q5, were tested against 210 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC50/MIC90 values (in μg/ml) were as follows: Q1, 0.5/2; Q2, 1/4; Q3, 2/4; Q4, 0.06/0.25; and Q5, 0.125/0.5. Several strains with high MIC values (from 8 to >32 μg/ml) for some of these compounds exhibited amino acid changes in the penicillin-binding proteins, which are targeted by these antibacterials.
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