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Kumar G, Seboletswe P, Mishra S, Manhas N, Ghumran S, Kerru N, Roquet-Banères F, Foubert M, Kremer L, Bhargava G, Singh P. Isoniazid-Dihydropyrimidinone Molecular Hybrids: Design, Synthesis, Antitubercular Activity, and Cytotoxicity Investigations with Computational Validation. ChemMedChem 2025:e2400949. [PMID: 40067058 DOI: 10.1002/cmdc.202400949] [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: 11/25/2024] [Revised: 03/10/2025] [Accepted: 03/10/2025] [Indexed: 04/03/2025]
Abstract
A new series of isoniazid-dihydropyrimidinone molecular hybrids (8a-8n) were designed, synthesized and structurally characterized using different spectroscopic techniques viz., Fourier transform infrared spectroscopy, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry followed by their antitubercular evaluation including their precursors (4a-4n), and a standard antitubercular drug (isoniazid; INH). The molecular hybrids particularly 8g (minimum inhibitory concentration (MIC) = 6.25 μg mL-1), 8h (MIC = 1.56 μg mL-1), 8k (MIC = 0.78 μg mL-1), 8l (MIC = 6.25 μg mL-1), and 8n (MIC = 0.39 μg mL-1) demonstrated the most potent inhibitory activity against wild-type M. tuberculosis mc26230, disclosing 8n as the most potent compound in the series. However, the potent compounds lost their activity against three INH-resistant M. tuberculosis strains mutated in katG. The more efficient compounds (8h, 8k, and 8n) were subsequently evaluated for their cytotoxicity against the THP-1 human monocytic cell line. Furthermore, the stability studies of the most potent compound carried out using 1H NMR, UV-visible, and liquid chromatography-mass spectrometry revealed their structural integrity. Finally, in silico molecular docking simulations were conducted to explore the binding orientations of the potent compounds in the active site of the target protein InhA while ADME/T (absorption, distribution, metabolism, excretion, and toxicity) and global reactivity parameters were explored to determine their drug-likeness and stability profiles, respectively.
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Affiliation(s)
- Gobind Kumar
- School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban, 4000, South Africa
| | - Pule Seboletswe
- School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban, 4000, South Africa
| | - Sahil Mishra
- School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban, 4000, South Africa
| | - Neha Manhas
- School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban, 4000, South Africa
| | - Safiyah Ghumran
- School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban, 4000, South Africa
| | - Nagaraju Kerru
- School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban, 4000, South Africa
| | - Françoise Roquet-Banères
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293, Montpellier, France
| | - Maëlle Foubert
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293, Montpellier, France
| | - Laurent Kremer
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293, Montpellier, France
- INSERM, IRIM, 34293, Montpellier, France
| | - Gaurav Bhargava
- Department of Chemical Sciences, I. K. Gujral Punjab Technical University, Kapurthala, Punjab, 144603, India
| | - Parvesh Singh
- School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban, 4000, South Africa
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2
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Song HY, Yoo BG, Lee Y, Lim JY, Gu EJ, Jeon J, Byun EB. Isoniazid and nicotinic hydrazide hybrids mitigate trehalose-6,6'-dimycolate-induced inflammatory responses and pulmonary granulomas via Syk/PI3K pathways: A promising host-directed therapy for tuberculosis. Biomed Pharmacother 2025; 183:117798. [PMID: 39764922 DOI: 10.1016/j.biopha.2024.117798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/12/2024] [Accepted: 12/27/2024] [Indexed: 02/08/2025] Open
Abstract
Granulomas, dense clusters of immune cells and bacteria, are critical barriers in tuberculosis (TB) treatment. Recent advancements in TB management have highlighted granuloma control as a potential host-directed therapy (HDT) strategy. Although isoniazid (INH) is the first-line drug for TB therapy, its efficacy is limited to non-replicating Mycobacterium tuberculosis (Mtb) under granulomatous conditions, necessitating the development of more effective derivatives. In this study, hybrid compounds of isoniazid, designated as INH-D1 and INH-D2, were synthesized and evaluated for their effects on controlling inflammatory responses and pulmonary granuloma lesions induced by trehalose-6,6'-dimycolate (TDM), a glycolipid of Mtb. Both INH-D1 and INH-D2 demonstrated stronger inhibitory effects on inflammatory mediators (TNF-α, interleukin-6, co-stimulatory molecules, and MHC class I) in TDM-stimulated macrophages compared to original INH. These anti-inflammatory effects were mediated by the inhibition of Syk, p38, PI3K, and NF-κB transcription. INH-D1 and INH-D2 exhibited stronger binding energies to Syk and PI3Kα/β than INH, which are known as proximal kinases and key mediator in TDM-mediated inflammatory responses. Oral administration of INH-D2 successfully relieved TDM-induced pulmonary granuloma pathology by reducing innate immune cell infiltration, hypoxic conditions in the lungs, and systemic inflammation by decreasing serum cytokines and chemokines. In contrast, original INH and INH-D1 did not effectively alleviate pulmonary granuloma pathology. These findings demonstrate that the novel molecule INH-D2 is effective in treating pulmonary granulomas owing to its strong anti-inflammatory effects, highlighting it as a promising HDT candidate for the management of pulmonary tuberculosis, thereby providing a strategic alternative to standard anti-TB antibiotics.
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Affiliation(s)
- Ha-Yeon Song
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea
| | - Bo-Gyeong Yoo
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea; Department of Food Science and Technology, Kongju National University, Yesan 32439, Republic of Korea
| | - Yuna Lee
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea
| | - Jae Yoon Lim
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea; Department of Food and Nutrition, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Eun Ji Gu
- Department of Applied Chemistry, College of Engineering, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jongho Jeon
- Department of Applied Chemistry, College of Engineering, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Eui-Baek Byun
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea.
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3
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Ofori-Anyinam B, Hamblin M, Coldren ML, Li B, Mereddy G, Shaikh M, Shah A, Grady C, Ranu N, Lu S, Blainey PC, Ma S, Collins JJ, Yang JH. Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline. Nat Commun 2024; 15:9792. [PMID: 39537610 PMCID: PMC11561320 DOI: 10.1038/s41467-024-53933-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Multidrug-resistant tuberculosis (MDR-TB), defined as resistance to the first-line drugs isoniazid and rifampin, is a growing source of global mortality and threatens global control of tuberculosis disease. The diarylquinoline bedaquiline has recently emerged as a highly efficacious drug against MDR-TB and kills Mycobacterium tuberculosis by inhibiting mycobacterial ATP synthase. However, the mechanisms underlying bedaquiline's efficacy against MDR-TB remain unknown. Here we investigate bedaquiline hyper-susceptibility in drug-resistant Mycobacterium tuberculosis using systems biology approaches. We discovered that MDR clinical isolates are commonly sensitized to bedaquiline. This hypersensitization is caused by several physiological changes induced by deficient catalase activity. These include enhanced accumulation of reactive oxygen species, increased susceptibility to DNA damage, induction of sensitizing transcriptional programs, and metabolic repression of several biosynthetic pathways. In this work we demonstrate how resistance-associated changes in bacterial physiology can mechanistically induce collateral antimicrobial drug sensitivity and reveal druggable vulnerabilities in antimicrobial resistant pathogens.
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Affiliation(s)
- Boatema Ofori-Anyinam
- Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Meagan Hamblin
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Eversana Consulting, Boston, MA, 02120, USA
| | - Miranda L Coldren
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98105, USA
| | - Barry Li
- Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Gautam Mereddy
- Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Mustafa Shaikh
- Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Avi Shah
- Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Courtney Grady
- Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
- Public Health Research Institute, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Navpreet Ranu
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- insitro, South San Francisco, CA, 94080, USA
| | - Sean Lu
- Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Paul C Blainey
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Koch Institute of Integrative Cancer Research at MIT, Cambridge, MA, 02139, USA
| | - Shuyi Ma
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98105, USA
- Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA
- Department of Chemical Engineering, University of Washington, Seattle, WA, 98195, USA
- Pathobiology Graduate Program, Department of Global Health, University of Washington, Seattle, WA, 98195, USA
| | - James J Collins
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Jason H Yang
- Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA.
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA.
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4
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Megawati D, Armitige LY, Tazi L. Differential Host Gene Expression in Response to Infection by Different Mycobacterium tuberculosis Strains-A Pilot Study. Microorganisms 2024; 12:2146. [PMID: 39597535 PMCID: PMC11596623 DOI: 10.3390/microorganisms12112146] [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: 09/09/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/29/2024] Open
Abstract
Tuberculosis (TB) represents a global public health threat and is a leading cause of morbidity and mortality worldwide. Effective control of TB is complicated with the emergence of multidrug resistance. Yet, there is a fundamental gap in understanding the complex and dynamic interactions between different Mycobacterium tuberculosis strains and the host. In this pilot study, we investigated the host immune response to different M. tuberculosis strains, including drug-sensitive avirulent or virulent, and rifampin-resistant or isoniazid-resistant virulent strains in human THP-1 cells. We identified major differences in the gene expression profiles in response to infection with these strains. The expression of IDO1 and IL-1β in the infected cells was stronger in all virulent M. tuberculosis strains. The most striking result was the overexpression of many interferon-stimulated genes (ISGs) in cells infected with the isoniazid-resistant strain, compared to the rifampin-resistant and the drug-sensitive strains. Our data indicate that infection with the isoniazid-resistant M. tuberculosis strain preferentially resulted in cGAS-STING/STAT1 activation, which induced a characteristic host immune response. These findings reveal complex gene signatures and a dynamic variation in the immune response to infection by different M. tuberculosis strains.
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Affiliation(s)
- Dewi Megawati
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616, USA;
- Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Warmadewa University, Denpasar 80239, Bali, Indonesia
| | | | - Loubna Tazi
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616, USA;
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Shekhar, Roquet-Banères F, Anand A, Kremer L, Kumar V. Rational design and microwave-promoted synthesis of triclosan-based dimers: targeting InhA for anti-mycobacterial profiling. ROYAL SOCIETY OPEN SCIENCE 2024; 11:240676. [PMID: 39392739 PMCID: PMC11461061 DOI: 10.1098/rsos.240676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/02/2024] [Accepted: 08/06/2024] [Indexed: 10/13/2024]
Abstract
A set of alkyl-/1H-1,2,3-triazole-based dimers was strategically designed and synthesized to evaluate their in vitro anti-mycobacterial activities against Mycobacterium tuberculosis and the non-tuberculous Mycobacterium abscessus strains. Systematic variations in the nature (alkyl/1H-1,2,3-triazole) and positioning of the linker were implemented based on the docking scores observed in the binding sites identified in the crystal structures of InhA from M. tuberculosis and M. abscessus. However, the in vitro evaluation results revealed that the synthesized compounds did not exhibit inhibitory effects on the growth of mycobacteria, even at the highest tested concentrations. The elevated lipophilicity values determined through ADMET studies for these synthesized dimers might be a contributing factor to their poor activity profiles.
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Affiliation(s)
- Shekhar
- Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab143005, India
| | - Francoise Roquet-Banères
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293 Montpellier, France
| | - Amit Anand
- Department of Chemistry, Khalsa College, Amritsar, Punjab143005, India
| | - Laurent Kremer
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293 Montpellier, France
- INSERM, IRIM, 34293 Montpellier, France
| | - Vipan Kumar
- Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab143005, India
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Al-Warhi T, Sabt A, Korycka-Machala M, Kassem AF, Shaldam MA, Ibrahim HAA, Kawka M, Dziadek B, Kuzioła M, Eldehna WM, Dziadek J. Benzenesulfonohydrazide-tethered non-fused and fused heterocycles as potential anti-mycobacterial agents targeting enoyl acyl carrier protein reductase (InhA) with antibiofilm activity. RSC Adv 2024; 14:30165-30179. [PMID: 39315015 PMCID: PMC11418391 DOI: 10.1039/d4ra05616g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/09/2024] [Indexed: 09/25/2024] Open
Abstract
Because resistant variants of the disease are always emerging, tuberculosis is a global issue that affects economies. New antitubercular medications should be developed, and this can be done by inhibiting druggable targets. Enoyl acyl carrier protein (ACP) reductase (InhA) is a crucial enzyme for the survival of Mycobacterium tuberculosis (MTB). In this study, a series of small molecules based on non-fused and fused heterocycles (pyridine, coumarin, quinoline, and indole) tethered with benzenesulfonohydrazide were prepared via an aza-Michael reaction exploiting a one-pot synthesis approach. The synthesized molecules (2-7) were evaluated for their activity against tubercle bacilli. Three analogues showed efficacy against tuberculosis, with compound 7 demonstrating a MIC value as low as 8 μg mL-1. Consequently, compounds 3 and 7 successfully hindered the growth of mycobacteria in human monocyte-derived macrophages (MDMs), demonstrating their ability to penetrate human professional phagocytes. Furthermore, they restricted the ability of mycobacteria to produce biofilms. In addition, the inhibitory effects of compounds 3 and 7 against InhA were assessed. Compound 7 exhibited the best efficacy, with an IC50 value of 0.91 μM. The findings showed that the sulfonamide and methyl ester's carbonyl functionalities were engaged in hydrogen bonding with the essential Ile194 and Tyr158 residues, respectively.
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Affiliation(s)
- Tarfah Al-Warhi
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University Riyadh Saudi Arabia
| | - Ahmed Sabt
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre Dokki Cairo 12622 Egypt
| | - Małgorzata Korycka-Machala
- Laboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences Lodz Poland
| | - Asmaa F Kassem
- Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University Al-Kharj 11942 Saudi Arabia
| | - Moataz A Shaldam
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University Kafrelsheikh 33516 Egypt
| | | | - Malwina Kawka
- Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz Lodz Poland
| | - Bożena Dziadek
- Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz Lodz Poland
| | - Magdalena Kuzioła
- Laboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences Lodz Poland
- Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences Lodz Poland
| | - Wagdy M Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University Kafrelsheikh 33516 Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria Canal El Mahmoudia St. Alexandria 21648 Egypt
| | - Jarosław Dziadek
- Laboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences Lodz Poland
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Choudhery S, DeJesus MA, Srinivasan A, Rock J, Schnappinger D, Ioerger TR. A dose-response model for statistical analysis of chemical genetic interactions in CRISPRi screens. PLoS Comput Biol 2024; 20:e1011408. [PMID: 38768228 PMCID: PMC11104602 DOI: 10.1371/journal.pcbi.1011408] [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: 08/02/2023] [Accepted: 04/22/2024] [Indexed: 05/22/2024] Open
Abstract
An important application of CRISPR interference (CRISPRi) technology is for identifying chemical-genetic interactions (CGIs). Discovery of genes that interact with exposure to antibiotics can yield insights to drug targets and mechanisms of action or resistance. The objective is to identify CRISPRi mutants whose relative abundance is suppressed (or enriched) in the presence of a drug when the target protein is depleted, reflecting synergistic behavior. Different sgRNAs for a given target can induce a wide range of protein depletion and differential effects on growth rate. The effect of sgRNA strength can be partially predicted based on sequence features. However, the actual growth phenotype depends on the sensitivity of cells to depletion of the target protein. For essential genes, sgRNA efficiency can be empirically measured by quantifying effects on growth rate. We observe that the most efficient sgRNAs are not always optimal for detecting synergies with drugs. sgRNA efficiency interacts in a non-linear way with drug sensitivity, producing an effect where the concentration-dependence is maximized for sgRNAs of intermediate strength (and less so for sgRNAs that induce too much or too little target depletion). To capture this interaction, we propose a novel statistical method called CRISPRi-DR (for Dose-Response model) that incorporates both sgRNA efficiencies and drug concentrations in a modified dose-response equation. We use CRISPRi-DR to re-analyze data from a recent CGI experiment in Mycobacterium tuberculosis to identify genes that interact with antibiotics. This approach can be generalized to non-CGI datasets, which we show via an CRISPRi dataset for E. coli growth on different carbon sources. The performance is competitive with the best of several related analytical methods. However, for noisier datasets, some of these methods generate far more significant interactions, likely including many false positives, whereas CRISPRi-DR maintains higher precision, which we observed in both empirical and simulated data.
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Affiliation(s)
- Sanjeevani Choudhery
- Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, United States of America
| | - Michael A. DeJesus
- Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, New York, United States of America
| | - Aarthi Srinivasan
- Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, United States of America
| | - Jeremy Rock
- Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, New York, United States of America
| | - Dirk Schnappinger
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America
| | - Thomas R. Ioerger
- Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, United States of America
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8
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Tafess K, Ng TTL, Tam KKG, Leung KSS, Leung JSL, Lee LK, Lao HY, Chan CTM, Yam WC, Wong SSY, Lau TCK, Siu GKH. Genetic mechanisms of co-emergence of INH-resistant Mycobacterium tuberculosis strains during the standard course of antituberculosis therapy. Microbiol Spectr 2024; 12:e0213323. [PMID: 38466098 PMCID: PMC10986572 DOI: 10.1128/spectrum.02133-23] [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: 08/22/2023] [Accepted: 01/30/2024] [Indexed: 03/12/2024] Open
Abstract
The incidence of isoniazid (INH) resistant Mycobacterium tuberculosis is increasing globally. This study aimed to identify the molecular mechanisms behind the development of INH resistance in M. tuberculosis strains collected from the same patients during the standard course of treatment. Three M. tuberculosis strains were collected from a patient before and during antituberculosis (anti-TB) therapy. The strains were characterized using phenotypic drug susceptibility tests, Mycobacterial Interspersed Repeated Unit-Variable-Number Tandem Repeats (MIRU-VNTR), and whole-genome sequencing (WGS) to identify mutations associated with INH resistance. To validate the role of the novel mutations in INH resistance, the mutated katG genes were electroporated into a KatG-deleted M. tuberculosis strain (GA03). Three-dimensional structures of mutated KatG were modeled to predict their impact on INH binding. The pre-treatment strain was susceptible to INH. However, two INH-resistant strains were isolated from the patient after anti-TB therapy. MIRU-VNTR and WGS revealed that the three strains were clonally identical. A missense mutation (P232L) and a nonsense mutation (Q461Stop) were identified in the katG of the two post-treatment strains, respectively. Transformation experiments showed that katG of the pre-treatment strain restored INH susceptibility in GA03, whereas the mutated katG genes from the post-treatment strains rendered negative catalase activity and INH resistance. The protein model indicated that P232L reduced INH-KatG binding affinity while Q461Stop truncated gene transcription. Our results showed that the two katG mutations, P232L and Q461Stop, accounted for the co-emergence of INH-resistant clones during anti-TB therapy. The inclusion of these mutations in the design of molecular assays could increase the diagnostic performance.IMPORTANCEThe evolution of drug-resistant strains of Mycobacterium tuberculosis within the lung lesions of a patient has a detrimental impact on treatment outcomes. This is particularly concerning for isoniazid (INH), which is the most potent first-line antimycobacterial drug. However, the precise genetic factors responsible for drug resistance in patients have not been fully elucidated, with approximately 15% of INH-resistant strains harboring unknown genetic factors. This raises concerns about the emergence of drug-resistant clones within patients, further contributing to the global epidemic of resistance. In this study, we revealed the presence of two novel katG mutations, which emerged independently due to the stress exerted by antituberculosis (anti-TB) treatment on a parental strain. Importantly, we experimentally demonstrated the functional significance of both mutations in conferring resistance to INH. Overall, this research sheds light on the genetic mechanisms underlying the evolution of INH resistance within patients and provides valuable insights for improving diagnostic performance by targeting specific mutations.
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Affiliation(s)
- Ketema Tafess
- Department of Applied Biology, School of Applied Natural Sciences, Adama Science and Technology University, Adama, Ethiopia
- Institute of Pharmaceutical Sciences, Adama Science and Technology University, Adama, Ethiopia
| | - Timothy Ting-Leung Ng
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Kingsley King-Gee Tam
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Kenneth Siu-Sing Leung
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Jake Siu-Lun Leung
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Lam-Kwong Lee
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Hiu Yin Lao
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Chloe Toi-Mei Chan
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Wing-Cheong Yam
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Samson Sai Yin Wong
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Terrence Chi-Kwong Lau
- Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Gilman Kit-Hang Siu
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
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9
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Singha B, Murmu S, Nair T, Rawat RS, Sharma AK, Soni V. Metabolic Rewiring of Mycobacterium tuberculosis upon Drug Treatment and Antibiotics Resistance. Metabolites 2024; 14:63. [PMID: 38248866 PMCID: PMC10820029 DOI: 10.3390/metabo14010063] [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: 12/25/2023] [Revised: 01/09/2024] [Accepted: 01/16/2024] [Indexed: 01/23/2024] Open
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge, further compounded by the issue of antimicrobial resistance (AMR). AMR is a result of several system-level molecular rearrangements enabling bacteria to evolve with better survival capacities: metabolic rewiring is one of them. In this review, we present a detailed analysis of the metabolic rewiring of Mtb in response to anti-TB drugs and elucidate the dynamic mechanisms of bacterial metabolism contributing to drug efficacy and resistance. We have discussed the current state of AMR, its role in the prevalence of the disease, and the limitations of current anti-TB drug regimens. Further, the concept of metabolic rewiring is defined, underscoring its relevance in understanding drug resistance and the biotransformation of drugs by Mtb. The review proceeds to discuss the metabolic adaptations of Mtb to drug treatment, and the pleiotropic effects of anti-TB drugs on Mtb metabolism. Next, the association between metabolic changes and antimycobacterial resistance, including intrinsic and acquired drug resistance, is discussed. The review concludes by summarizing the challenges of anti-TB treatment from a metabolic viewpoint, justifying the need for this discussion in the context of novel drug discovery, repositioning, and repurposing to control AMR in TB.
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Affiliation(s)
- Biplab Singha
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA;
| | - Sumit Murmu
- Regional Centre of Biotechnology, Faridabad 121001, India;
| | - Tripti Nair
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA;
| | - Rahul Singh Rawat
- Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi 110067, India;
| | - Aditya Kumar Sharma
- Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Vijay Soni
- Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
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10
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Jain A, Kumar R, Mothsra P, Sharma AK, Singh AK, Kumar Y. Recent Biochemical Advances in Antitubercular Drugs: Challenges and Future. Curr Top Med Chem 2024; 24:1829-1855. [PMID: 38919089 DOI: 10.2174/0115680266286294240610102911] [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: 12/31/2023] [Revised: 03/29/2024] [Accepted: 04/29/2024] [Indexed: 06/27/2024]
Abstract
Tuberculosis (TB) is one of the leading causes of death world-wide after AIDS. It infects around one-third of global population and approximately two million people die annually from this disease because it is a very contagious disease spread by Mycobacterium tuberculosis. The increasing number of drug-resistant strains and the failure of conventional treatments against this strain are the challenges of the coming decades. New therapeutic techniques aim to confirm cure without deterioration, to reduce deaths, contagions and the formation of drug-resistant strains. A plethora of new diagnostic tests are available to diagnose the active tuberculosis, screen latent M. tuberculosis infection, and to identify drug-resistant strains of M. tuberculosis. When effective prevention strategies do not prevail, high rates of early case detection and successive cures to control TB emergence would not be possible. In this review, we discussed the structural features of M. tuberculosis, Multi drug resistance tuberculosis (MDR-TB), extremely drug-resistant tuberculosis (XDR-TB), the mechanism of M. tuberculosis infection, the mode of action of first and second-line antitubercular drugs, the mechanism of resistance to the existing drugs, compounds in preclinical and clinical trial and drugs presently available for the treatment of tuberculosis. Moreover, the new diagnostic techniques to detect M. tuberculosis are also discussed in this review.
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Affiliation(s)
- Akanksha Jain
- Department of Food and Nutrition, Bhagini Nivedita College, University of Delhi, Kair Near Najafgarh, Delhi, 110043, India
| | - Rajesh Kumar
- P.G. Department of Chemistry, R.D.S. College, B.R.A. Bihar University, Muzaffarpur, 842002, India
| | - Poonam Mothsra
- Department of Chemistry, Bhagini Nivedita College, University of Delhi, Kair Near Najafgarh, Delhi, 110043, India
| | - Atul Kumar Sharma
- Department of Chemistry, Deshbandhu College, University of Delhi, 110019, India
| | - Anil Kumar Singh
- Department of Chemistry, School of Physical Sciences, Mahatma Gandhi Central University, Motihari, Bihar, 845401, India
| | - Yogesh Kumar
- Department of Chemistry, Bhagini Nivedita College, University of Delhi, Kair Near Najafgarh, Delhi, 110043, India
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11
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Chang M, Venkatasubramanian S, Barrett H, Urdahl KB, Weigel KM, Cangelosi GA, Shah JA, Saha A, Feng L, Adams KN, Sherman DR, Smith N, Seshadri C, Kublin JG, Murphy SC. Molecular detection of pre-ribosomal RNAs of Mycobacterium bovis bacille Calmette-Guérin and Mycobacterium tuberculosis to enhance pre-clinical tuberculosis drug and vaccine development. Diagn Microbiol Infect Dis 2024; 108:116106. [PMID: 37931386 PMCID: PMC10729053 DOI: 10.1016/j.diagmicrobio.2023.116106] [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: 06/29/2023] [Revised: 10/03/2023] [Accepted: 10/10/2023] [Indexed: 11/08/2023]
Abstract
Efforts are underway globally to develop effective vaccines and drugs against M. tuberculosis (Mtb) to reduce the morbidity and mortality of tuberculosis. Improving detection of slow-growing mycobacteria could simplify and accelerate efficacy studies of vaccines and drugs in animal models and human clinical trials. Here, a real-time reverse transcription PCR (RT-PCR) assay was developed to detect pre-ribosomal RNA (pre-rRNA) of Mycobacterium bovis bacille Calmette-Guérin (BCG) and Mtb. This pre-rRNA biomarker is indicative of bacterial viability. In two different mouse models, the presence of pre-rRNA from BCG and Mtb in ex vivo tissues showed excellent agreement with slower culture-based colony-forming unit assays. The addition of a brief nutritional stimulation prior to molecular viability testing further differentiated viable but dormant mycobacteria from dead mycobacteria. This research has set the stage to evaluate pre-rRNA as a BCG and/or Mtb infection biomarker in future drug and vaccine clinical studies.
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Affiliation(s)
- Ming Chang
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
| | | | - Holly Barrett
- Seattle Children's Research Institute, Seattle, WA, USA
| | - Kevin B Urdahl
- Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Immunology, University of Washington, Seattle, WA, USA
| | - Kris M Weigel
- Department of Environmental & Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Gerard A Cangelosi
- Department of Environmental & Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Javeed A Shah
- Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA; Veterans' Affairs Puget Sound Healthcare System, Seattle, WA, USA
| | - Aparajita Saha
- Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - Libing Feng
- Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - Kristin N Adams
- Department of Microbiology, University of Washington, Seattle, WA, USA
| | - David R Sherman
- Department of Microbiology, University of Washington, Seattle, WA, USA
| | - Nahum Smith
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Chetan Seshadri
- Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - James G Kublin
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA
| | - Sean C Murphy
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA; Department of Microbiology, University of Washington, Seattle, WA, USA.
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12
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Schami A, Islam MN, Belisle JT, Torrelles JB. Drug-resistant strains of Mycobacterium tuberculosis: cell envelope profiles and interactions with the host. Front Cell Infect Microbiol 2023; 13:1274175. [PMID: 38029252 PMCID: PMC10664572 DOI: 10.3389/fcimb.2023.1274175] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/02/2023] [Indexed: 12/01/2023] Open
Abstract
In the past few decades, drug-resistant (DR) strains of Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), have become increasingly prevalent and pose a threat to worldwide public health. These strains range from multi (MDR) to extensively (XDR) drug-resistant, making them very difficult to treat. Further, the current and future impact of the Coronavirus Disease 2019 (COVID-19) pandemic on the development of DR-TB is still unknown. Although exhaustive studies have been conducted depicting the uniqueness of the M.tb cell envelope, little is known about how its composition changes in relation to drug resistance acquisition. This knowledge is critical to understanding the capacity of DR-M.tb strains to resist anti-TB drugs, and to inform us on the future design of anti-TB drugs to combat these difficult-to-treat strains. In this review, we discuss the complexities of the M.tb cell envelope along with recent studies investigating how M.tb structurally and biochemically changes in relation to drug resistance. Further, we will describe what is currently known about the influence of M.tb drug resistance on infection outcomes, focusing on its impact on fitness, persister-bacteria, and subclinical TB.
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Affiliation(s)
- Alyssa Schami
- Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, United States
- Integrated Biomedical Sciences Program, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - M. Nurul Islam
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States
| | - John T. Belisle
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States
| | - Jordi B. Torrelles
- Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, United States
- International Center for the Advancement of Research & Education, International Center for the Advancement of Research & Education, Texas Biomedical Research Institute, San Antonio, TX, United States
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13
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Ofori-Anyinam N, Hamblin M, Coldren ML, Li B, Mereddy G, Shaikh M, Shah A, Ranu N, Lu S, Blainey PC, Ma S, Collins JJ, Yang JH. KatG catalase deficiency confers bedaquiline hyper-susceptibility to isoniazid resistant Mycobacterium tuberculosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.17.562707. [PMID: 37905073 PMCID: PMC10614911 DOI: 10.1101/2023.10.17.562707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Multidrug-resistant tuberculosis (MDR-TB) is a growing source of global mortality and threatens global control of tuberculosis (TB) disease. The diarylquinoline bedaquiline (BDQ) recently emerged as a highly efficacious drug against MDR-TB, defined as resistance to the first-line drugs isoniazid (INH) and rifampin. INH resistance is primarily caused by loss-of-function mutations in the catalase KatG, but mechanisms underlying BDQ's efficacy against MDR-TB remain unknown. Here we employ a systems biology approach to investigate BDQ hyper-susceptibility in INH-resistant Mycobacterium tuberculosis . We found hyper-susceptibility to BDQ in INH-resistant cells is due to several physiological changes induced by KatG deficiency, including increased susceptibility to reactive oxygen species and DNA damage, remodeling of transcriptional programs, and metabolic repression of folate biosynthesis. We demonstrate BDQ hyper-susceptibility is common in INH-resistant clinical isolates. Collectively, these results highlight how altered bacterial physiology can impact drug efficacy in drug-resistant bacteria.
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14
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Koleske BN, Jacobs WR, Bishai WR. The Mycobacterium tuberculosis genome at 25 years: lessons and lingering questions. J Clin Invest 2023; 133:e173156. [PMID: 37781921 PMCID: PMC10541200 DOI: 10.1172/jci173156] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023] Open
Abstract
First achieved in 1998 by Cole et al., the complete genome sequence of Mycobacterium tuberculosis continues to provide an invaluable resource to understand tuberculosis (TB), the leading cause of global infectious disease mortality. At the 25-year anniversary of this accomplishment, we describe how insights gleaned from the M. tuberculosis genome have led to vital tools for TB research, epidemiology, and clinical practice. The increasing accessibility of whole-genome sequencing across research and clinical settings has improved our ability to predict antibacterial susceptibility, to track epidemics at the level of individual outbreaks and wider historical trends, to query the efficacy of the bacille Calmette-Guérin (BCG) vaccine, and to uncover targets for novel antitubercular therapeutics. Likewise, we discuss several recent efforts to extract further discoveries from this powerful resource.
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Affiliation(s)
- Benjamin N. Koleske
- Center for Tuberculosis Research, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - William R. Jacobs
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - William R. Bishai
- Center for Tuberculosis Research, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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15
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Sarkar S, Mayer Bridwell AE, Good JAD, Wang ER, McKee SR, Valenta J, Harrison GA, Flentie KN, Henry FL, Wixe T, Demirel P, Vagolu SK, Chatagnon J, Machelart A, Brodin P, Tønjum T, Stallings CL, Almqvist F. Design, Synthesis, and Evaluation of Novel Δ 2-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant. J Med Chem 2023; 66:11056-11077. [PMID: 37485869 PMCID: PMC10461229 DOI: 10.1021/acs.jmedchem.3c00358] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Indexed: 07/25/2023]
Abstract
Mycobacterium tuberculosis (Mtb) drug resistance poses an alarming threat to global tuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, 17h and 17j. 17h and 17j inhibited Mtb respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtb mutant, and more effectively inhibited intracellular Mtb replication than C10. The (-)17j enantiomer showed further enhanced activity compared to its enantiomer and the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development against drug-resistant Mtb.
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Affiliation(s)
- Souvik Sarkar
- Department
of Chemistry, Umeå University, SE-90187 Umeå, Sweden
| | - Anne E. Mayer Bridwell
- Department
of Molecular Microbiology, Center for Women’s Infectious Disease
Research, Washington University School of
Medicine, St. Louis, 63110 Missouri, United States
| | | | - Erin R. Wang
- Department
of Molecular Microbiology, Center for Women’s Infectious Disease
Research, Washington University School of
Medicine, St. Louis, 63110 Missouri, United States
| | - Samuel R. McKee
- Department
of Molecular Microbiology, Center for Women’s Infectious Disease
Research, Washington University School of
Medicine, St. Louis, 63110 Missouri, United States
| | - Joy Valenta
- Department
of Molecular Microbiology, Center for Women’s Infectious Disease
Research, Washington University School of
Medicine, St. Louis, 63110 Missouri, United States
| | - Gregory A. Harrison
- Department
of Molecular Microbiology, Center for Women’s Infectious Disease
Research, Washington University School of
Medicine, St. Louis, 63110 Missouri, United States
| | - Kelly N. Flentie
- Department
of Molecular Microbiology, Center for Women’s Infectious Disease
Research, Washington University School of
Medicine, St. Louis, 63110 Missouri, United States
| | - Frederick L. Henry
- Department
of Molecular Microbiology, Center for Women’s Infectious Disease
Research, Washington University School of
Medicine, St. Louis, 63110 Missouri, United States
| | - Torbjörn Wixe
- Department
of Chemistry, Umeå University, SE-90187 Umeå, Sweden
| | - Peter Demirel
- Department
of Chemistry, Umeå University, SE-90187 Umeå, Sweden
| | - Siva K. Vagolu
- Department
of Microbiology, University of Oslo, N-0316 Oslo, Norway
| | - Jonathan Chatagnon
- University
Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR
9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Arnaud Machelart
- University
Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR
9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Priscille Brodin
- University
Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR
9017-CIIL-Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Tone Tønjum
- Department
of Microbiology, University of Oslo, N-0316 Oslo, Norway
- Oslo
University Hospital, N-0424 Oslo, Norway
| | - Christina L. Stallings
- Department
of Molecular Microbiology, Center for Women’s Infectious Disease
Research, Washington University School of
Medicine, St. Louis, 63110 Missouri, United States
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16
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Sampiron EG, Calsavara LL, Baldin VP, Montaholi DC, Leme ALD, Namba DY, Alves Olher VG, Caleffi-Ferraciolli KR, Cardoso RF, Siqueira VLD, Vandresen F, Scodro RBDL. Isoniazid-N-acylhydrazones as promising compounds for the anti-tuberculosis treatment. Tuberculosis (Edinb) 2023; 141:102363. [PMID: 37311289 DOI: 10.1016/j.tube.2023.102363] [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: 03/28/2023] [Revised: 05/29/2023] [Accepted: 06/05/2023] [Indexed: 06/15/2023]
Abstract
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis complex, still presents significant numbers of incidence and mortality, in addition to several cases of drug resistance. Resistance, especially to isoniazid, which is one of the main drugs used in the treatment, has increased. In this context, N-acylhydrazones derived from isoniazid have shown important anti-Mycobacterium tuberculosis activity. Hence, this work aimed to determine the anti-TB potential of 11 isoniazid-N-acylhydrazones (INH-acylhydrazones). For this purpose, the determination of minimum inhibitory concentration (MIC) against M. tuberculosis H37Rv and clinical isolates was carried out. Drug combination, minimum bactericidal concentration, cytotoxicity, and in silico parameters were also performed. INH-acylhydrazones (2), (8), and (9) had MIC for M. tuberculosis H37Rv similar to or lower than isoniazid, and bactericidal activity was observed. In addition, these compounds showed low cytotoxicity, with a selectivity index greater than 3,000. Interesting results were also obtained in the drug combination assay, with synergistic combinations with isoniazid, ethambutol, and rifampicin. In the in silico study, INH-acylhydrazones behaved similarly to INH, but with improvements in some aspects. Based on these findings, it is concluded that compounds (2), (8), and (9) are considered promising scaffolds and warrant further investigation for designing future antimicrobial drugs.
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Affiliation(s)
- Eloísa Gibin Sampiron
- Postgraduate Program in Health Sciences, State University of Maringá (UEM), Maringá, Paraná, 87020-900, Brazil.
| | | | | | - Débora Cássia Montaholi
- Postgraduate Program in Health Sciences, State University of Maringá (UEM), Maringá, Paraná, 87020-900, Brazil
| | | | - Danillo Yuji Namba
- Department of Chemistry, Federal Technological University of Paraná, Londrina, Paraná, 86057-970, Brazil
| | | | - Katiany Rizzieri Caleffi-Ferraciolli
- Postgraduate Program in Bioscience and Physiopathology, UEM, Maringá, Paraná, 87020-900, Brazil; Department of Clinical Analysis and Biomedicine, UEM, Maringá, Paraná, 87020-900, Brazil
| | - Rosilene Fressatti Cardoso
- Postgraduate Program in Health Sciences, State University of Maringá (UEM), Maringá, Paraná, 87020-900, Brazil; Postgraduate Program in Bioscience and Physiopathology, UEM, Maringá, Paraná, 87020-900, Brazil; Department of Clinical Analysis and Biomedicine, UEM, Maringá, Paraná, 87020-900, Brazil
| | - Vera Lucia Dias Siqueira
- Postgraduate Program in Bioscience and Physiopathology, UEM, Maringá, Paraná, 87020-900, Brazil; Department of Clinical Analysis and Biomedicine, UEM, Maringá, Paraná, 87020-900, Brazil
| | - Fábio Vandresen
- Department of Chemistry, Federal Technological University of Paraná, Londrina, Paraná, 86057-970, Brazil
| | - Regiane Bertin de Lima Scodro
- Postgraduate Program in Health Sciences, State University of Maringá (UEM), Maringá, Paraná, 87020-900, Brazil; Department of Clinical Analysis and Biomedicine, UEM, Maringá, Paraná, 87020-900, Brazil
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17
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Alcaraz M, Edwards TE, Kremer L. New therapeutic strategies for Mycobacterium abscessus pulmonary diseases - untapping the mycolic acid pathway. Expert Rev Anti Infect Ther 2023; 21:813-829. [PMID: 37314394 PMCID: PMC10529309 DOI: 10.1080/14787210.2023.2224563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/08/2023] [Indexed: 06/15/2023]
Abstract
INTRODUCTION Treatment options against Mycobacterium abscessus infections are very limited. New compounds are needed to cure M. abscessus pulmonary diseases. While the mycolic acid biosynthetic pathway has been largely exploited for the treatment of tuberculosis, this metabolic process has been overlooked in M. abscessus, although it offers many potential drug targets for the treatment of this opportunistic pathogen. AREAS COVERED Herein, the authors review the role of the MmpL3 membrane protein and the enoyl-ACP reductase InhA involved in the transport and synthesis of mycolic acids, respectively. They discuss their importance as two major vulnerable drug targets in M. abscessus and report the activity of MmpL3 and InhA inhibitors. In particular, they focus on NITD-916, a direct InhA inhibitor against M. abscessus, particularly warranted in the context of multidrug resistance. EXPERT OPINION There is an increasing body of evidence validating the mycolic acid pathway as an attractive drug target to be further exploited for M. abscessus lung disease treatments. The NITD-916 studies provide a proof-of-concept that direct inhibitors of InhA are efficient in vitro, in macrophages and in zebrafish. Future work is now required to improve the activity and pharmacological properties of these inhibitors and their evaluation in pre-clinical models.
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Affiliation(s)
- Matthéo Alcaraz
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293, Montpellier, France
| | - Thomas E. Edwards
- UCB BioSciences, Bainbridge Island, WA 98109 USA
- Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA 98109 USA
| | - Laurent Kremer
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 1919 route de Mende, 34293, Montpellier, France
- INSERM, IRIM, 34293 Montpellier, France
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18
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Wang X, Feng L, Li M, Dong W, Luo X, Shang D. Membrane-active and DNA binding related double-action antimycobacterial mechanism of antimicrobial peptide W3R6 and its synthetic analogs. Biochim Biophys Acta Gen Subj 2023:130415. [PMID: 37336295 DOI: 10.1016/j.bbagen.2023.130415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 06/21/2023]
Abstract
The emergence of multidrug- or extremely drug-resistant M. tuberculosis strains has made very few drugs available for current tuberculosis treatment. Antimicrobial peptides can be employed as a promising alternative strategy for TB treatment. Here, we designed and synthesized a series of peptide sequences based on the structure-activity relationships of natural sequences of antimicrobial peptides. The peptide W3R6 and its analogs were screened and found to have potent antimycobacterial activity against M. smegmatis, and no hemolytic activity against human erythrocytes. The evidence from the mechanism of action study indicated that W3R6 and its analogs can interact with the mycobacterial membrane in a lytic manner and form pores on the outer membrane of M. smegmatis. Significant colocalization of D-W3R6 with mycobacterial DNA was observed by confocal laser scanning microscopy and DNA retardation assays, which suggested that the antimycobacterial mechanism of action of the peptide was associated with the unprotected genomic DNA of M. smegmatis. In general, W3R6 and its analogs act on not only the mycobacterial membrane but also the genomic DNA in the cytoplasm, which makes it difficult for mycobacteria to generate resistance due to the peptides having two targets. In addition, the peptides can effectively eliminate M. smegmatis cells from infected macrophages. Our findings indicated that the antimicrobial peptide W3R6 could be a novel lead compound to overcome the threat from drug-resistant M. tuberculosis strains in the development of potent AMPs for TB therapeutic applications.
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Affiliation(s)
- Xiaorui Wang
- School of Life Science, Liaoning Normal University, Dalian 116081, China
| | - Liubin Feng
- College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Mengmiao Li
- School of Life Science, Liaoning Normal University, Dalian 116081, China
| | - Weibing Dong
- School of Life Science, Liaoning Normal University, Dalian 116081, China; Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116081, China.
| | - Xueyue Luo
- School of Life Science, Liaoning Normal University, Dalian 116081, China
| | - Dejing Shang
- School of Life Science, Liaoning Normal University, Dalian 116081, China; Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116081, China.
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19
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Kelley SP, Mossine VV, Mawhinney TP. Crystal structure of hydrazinium methanesulfonate, CH 8N 2O 3S. Z KRIST-NEW CRYST ST 2023. [DOI: 10.1515/ncrs-2023-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Abstract
CH8N2O3S, monoclinic, P21/c (no. 14), a = 9.7583 (16) Å, b = 5.4033 (9) Å, c = 10.4729 (17) Å, β = 110.483 (4)°, V = 517.29 (15) Å3, Z = 1, R
gt(F) = 0.0225, wR
ref(F
2) = 0.0649, T = 150 K.
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Affiliation(s)
- Steven P. Kelley
- Department of Chemistry Columbia , University of Missouri , Columbia , MO 65211 , USA
| | - Valeri V. Mossine
- Department of Biochemistry Columbia , University of Missouri , Columbia , MO 65211 , USA
| | - Thomas P. Mawhinney
- Department of Biochemistry Columbia , University of Missouri , Columbia , MO 65211 , USA
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20
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Sparks IL, Derbyshire KM, Jacobs WR, Morita YS. Mycobacterium smegmatis: The Vanguard of Mycobacterial Research. J Bacteriol 2023; 205:e0033722. [PMID: 36598232 PMCID: PMC9879119 DOI: 10.1128/jb.00337-22] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The genus Mycobacterium contains several slow-growing human pathogens, including Mycobacterium tuberculosis, Mycobacterium leprae, and Mycobacterium avium. Mycobacterium smegmatis is a nonpathogenic and fast growing species within this genus. In 1990, a mutant of M. smegmatis, designated mc2155, that could be transformed with episomal plasmids was isolated, elevating M. smegmatis to model status as the ideal surrogate for mycobacterial research. Classical bacterial models, such as Escherichia coli, were inadequate for mycobacteria research because they have low genetic conservation, different physiology, and lack the novel envelope structure that distinguishes the Mycobacterium genus. By contrast, M. smegmatis encodes thousands of conserved mycobacterial gene orthologs and has the same cell architecture and physiology. Dissection and characterization of conserved genes, structures, and processes in genetically tractable M. smegmatis mc2155 have since provided previously unattainable insights on these same features in its slow-growing relatives. Notably, tuberculosis (TB) drugs, including the first-line drugs isoniazid and ethambutol, are active against M. smegmatis, but not against E. coli, allowing the identification of their physiological targets. Furthermore, Bedaquiline, the first new TB drug in 40 years, was discovered through an M. smegmatis screen. M. smegmatis has become a model bacterium, not only for M. tuberculosis, but for all other Mycobacterium species and related genera. With a repertoire of bioinformatic and physical resources, including the recently established Mycobacterial Systems Resource, M. smegmatis will continue to accelerate mycobacterial research and advance the field of microbiology.
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Affiliation(s)
- Ian L. Sparks
- Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, USA
| | - Keith M. Derbyshire
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA
- Department of Biomedical Sciences, University at Albany, Albany, New York, USA
| | - William R. Jacobs
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Yasu S. Morita
- Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, USA
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, USA
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21
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Rossini NDO, Dias MVB. Mutations and insights into the molecular mechanisms of resistance of Mycobacterium tuberculosis to first-line. Genet Mol Biol 2023; 46:e20220261. [PMID: 36718771 PMCID: PMC9887390 DOI: 10.1590/1678-4685-gmb-2022-0261] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 12/18/2022] [Indexed: 01/28/2023] Open
Abstract
Genetically antimicrobial resistance in Mycobacterium tuberculosis is currently one of the most important aspects of tuberculosis, considering that there are emerging resistant strains for almost every known drug used for its treatment. There are multiple antimicrobials used for tuberculosis treatment, and the most effective ones are the first-line drugs, which include isoniazid, pyrazinamide, rifampicin, and ethambutol. In this context, understanding the mechanisms of action and resistance of these molecules is essential for proposing new therapies and strategies of treatment. Additionally, understanding how and where mutations arise conferring a resistance profile to the bacteria and their effect on bacterial metabolism is an important requisite to be taken in producing safer and less susceptible drugs to the emergence of resistance. In this review, we summarize the most recent literature regarding novel mutations reported between 2017 and 2022 and the advances in the molecular mechanisms of action and resistance against first-line drugs used in tuberculosis treatment, highlighting recent findings in pyrazinamide resistance involving PanD and, additionally, resistance-conferring mutations for novel drugs such as bedaquiline, pretomanid, delamanid and linezolid.
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Affiliation(s)
- Nicolas de Oliveira Rossini
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, SP, Brazil. Universidade de São PauloInstituto de Ciências BiomédicasDepartamento de MicrobiologiaSão PauloSPBrazil
| | - Marcio Vinicius Bertacine Dias
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, SP, Brazil. Universidade de São PauloInstituto de Ciências BiomédicasDepartamento de MicrobiologiaSão PauloSPBrazil
- University of Warwick, Department of Chemistry, Coventry, United Kingdom. University of WarwickDepartment of ChemistryCoventryUnited Kingdom
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22
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Zhou Z, Yang X, Huang T, Zheng J, Deng Z, Dai S, Lin S. Bifunctional NadC Homologue PyrZ Catalyzes Nicotinic Acid Formation in Pyridomycin Biosynthesis. ACS Chem Biol 2023; 18:141-150. [PMID: 36517246 DOI: 10.1021/acschembio.2c00773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Pyridomycin is a potent antimycobacterial natural product by specifically inhibiting InhA, a clinically validated antituberculosis drug discovery target. Pyridyl moieties of pyridomycin play an essential role in inhibiting InhA by occupying the reduced form of the nicotinamide adenine dinucleotide (NADH) cofactor binding site. Herein, we biochemically characterize PyrZ that is a multifunctional NadC homologue and catalyzes the successive formation, dephosphorylation, and ribose hydrolysis of nicotinic acid mononucleotide (NAMN) to generate nicotinic acid (NA), a biosynthetic precursor for the pyridyl moiety of pyridomycin. Crystal structures of PyrZ in complex with substrate quinolinic acid (QA) and the final product NA revealed a specific salt bridge formed between K184 and the C3-carboxyl group of QA. This interaction positions QA for accepting the phosphoribosyl group to generate NAMN, retains NAMN within the active site, and mediates its translocation to nucleophile D296 for dephosphorylation. Combining kinetic and thermodynamic analysis with site-directed mutagenesis, the catalytic mechanism of PyrZ dephosphorylation was proposed. Our study discovered an alternative and concise NA biosynthetic pathway involving a unique multifunctional enzyme.
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Affiliation(s)
- Zihua Zhou
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Xu Yang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Tingting Huang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Jianting Zheng
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Zixin Deng
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Shaobo Dai
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Shuangjun Lin
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.,Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, China
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23
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Edwards BD, Field SK. The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis. Drugs 2022; 82:1695-1715. [PMID: 36479687 PMCID: PMC9734533 DOI: 10.1007/s40265-022-01817-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2022] [Indexed: 12/12/2022]
Abstract
This article provides an encompassing review of the current pipeline of putative and developed treatments for tuberculosis, including multidrug-resistant strains. The review has organized each compound according to its site of activity. To provide context, mention of drugs within current recommended treatment regimens is made, thereafter followed by discussion on recently developed and upcoming molecules at established and novel targets. The review is designed to provide a clinically applicable understanding of the compounds that are deemed most currently relevant, including those already under clinical study and those that have shown promising pre-clinical results. An extensive review of the efficacy and safety data for key contemporary drugs already incorporated into treatment regimens, such as bedaquiline, pretomanid, and linezolid, is provided. The three levels of the bacterial cell wall (mycolic acid, arabinogalactan, and peptidoglycan layers) are highlighted and important compounds designed to target each layer are delineated. Amongst others, the highly optimistic and potent anti-mycobacterial activity of agents such as BTZ-043, PBTZ 169, and OPC-167832 are emphasized. The evolving spectrum of oxazolidinones, such as sutezolid, delpazolid, and TBI-223, all aiming to exceed the efficacy achieved with linezolid yet offer a safer alternative to the potential toxicity, are reviewed. New and exciting prospective agents with novel mechanisms of impact against TB, including 3-aminomethyl benzoxaboroles and telacebec, are underscored. We describe new diaryloquinolines in development, striving to build on the immense success of bedaquiline. Finally, we discuss some of these compounds that have shown encouraging additive or synergistic benefit when used in combination, providing some promise for the future in treating this ancient scourge.
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Affiliation(s)
- Brett D Edwards
- Division of Infectious Diseases and Tuberculosis Services, Alberta Health Services, Department of Medicine, Cumming School of Medicine, University of Calgary, Peter Lougheed Centre, 3500, 26 Avenue NE, Calgary, AB, T1Y6J4, Canada.
| | - Stephen K Field
- Division of Infectious Diseases and Tuberculosis Services, Alberta Health Services, Department of Medicine, Cumming School of Medicine, University of Calgary, Peter Lougheed Centre, 3500, 26 Avenue NE, Calgary, AB, T1Y6J4, Canada
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24
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Latent Tuberculosis: A Promising New Compound to Treat Non-Replicating and Intramacrophagic Mycobacteria. Biomedicines 2022; 10:biomedicines10102398. [PMID: 36289661 PMCID: PMC9598318 DOI: 10.3390/biomedicines10102398] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/23/2022] [Accepted: 09/11/2022] [Indexed: 11/26/2022] Open
Abstract
As a biologic reservoir of Mycobacterium tuberculosis (M. tb), one-quarter of the world population is infected with the well-known latent tuberculosis (LTBI). About 5–10% of LTBI patients will progress to active disease in the first years after primary infection and, despite using the recommended treatment, 20% can still reactivate the infection. A new LTBI treatment could minimize adverse effects and antibiotic resistance that can occur when the same drug is used to treat the latent and active disease. New hydrazones were evaluated, and they showed great inhibitory activity against intramacrophagic and non-replicating M. tb, commonly found at this stage of infection, in addition to bactericidal and narrow-spectrum activity. When tested against eukaryotic cells, the hydrazones showed great safety at different exposure times. In vitro, these compounds performed better than isoniazid and could be considered new candidates for LTBI treatment, which may promote greater engagement in its prescription and adherence.
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25
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Jacobs WR. A world without tuberculosis: moving from imagination to reality. J Clin Invest 2022; 132:162688. [PMID: 36106635 PMCID: PMC9479609 DOI: 10.1172/jci162688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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26
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Ragab AE, Badawy ET, Aboukhatwa SM, Abdel-Aziz MM, Kabbash A, Abo Elseoud KA. Isonicotinic acid N-oxide, from isoniazid biotransformation by Aspergillus niger, as an InhA inhibitor antituberculous agent against multiple and extensively resistant strains supported by in silico docking and ADME prediction. Nat Prod Res 2022; 37:1687-1692. [PMID: 35876096 DOI: 10.1080/14786419.2022.2103695] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Biotransformation of isoniazid produced isonicotinic acid (1), isonicotinic acid N-oxide (2), and isonicotinamide (3) which were isolated by column chromatography using silica gel and Sephadex LH 20 and elucidated using various spectroscopies. This is the first report for isolation of 2. Antituberculosis activity was evaluated against Mycobacterium tuberculosis strains: drug sensitive (DS), multiple drug resistant (MDR) and extensively drug resistant (XDR). 1-3 and isoniazid showed MICs of 63.49, 0.22, 15.98 and 0.88 µM, respectively, against the DS strain. For the MDR strain, 2 and 3 exhibited MICs of 28.06 and > 1000 µM, respectively, while 1 was inactive. Moreover, 2 had an MIC of 56.19 µM against XDR strain, while 1 and 3 were inactive. Docking simulation using enoyl ACP reductase (InhA) revealed favorable protein-ligand interactions. In silico study of pharmacokinetics and hepatotoxicity predicted 1-3 to have good oral bioavailability and 2 to have a lower hepatoxicity probability than isoniazid.
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Affiliation(s)
- Amany E. Ragab
- Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Ebtisam T. Badawy
- Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Shaimaa M. Aboukhatwa
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Marwa M. Abdel-Aziz
- The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
| | - Amal Kabbash
- Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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27
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Designing quinoline-isoniazid hybrids as potent anti-tubercular agents inhibiting mycolic acid biosynthesis. Eur J Med Chem 2022; 239:114531. [PMID: 35759907 DOI: 10.1016/j.ejmech.2022.114531] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 05/04/2022] [Accepted: 06/10/2022] [Indexed: 11/23/2022]
Abstract
Isoniazid is a cornerstone of modern tuberculosis (TB) therapy and targets the enoyl ACP reductase InhA, a key enzyme in mycolic acid biosynthesis. InhA is still a promising target for the development of new anti-TB drugs. Herein, we report the design, synthesis, and anti-tubercular activity of new isoniazid hybrids. Among these, 1H-1,2,3 triazole-tethered quinoline-isoniazid conjugates 16a to 16g exhibited high activity against Mycobacterium tuberculosis with minimal inhibitory concentrations in the 0.25-0.50 μg/mL range and were bactericidal in vitro. Importantly, these compounds were well tolerated at high doses on mammalian cells, leading to high selectivity indices. The hybrids were dependent on functional KatG production to inhibit mycolic acid biosynthesis. Moreover, overexpression of InhA in M. tuberculosis resulted in high resistance levels to 16a-16g and reduced mycolic acid biosynthesis inhibition, similar to isoniazid. Overall, these findings suggest that the synthesized quinoline-isoniazid hybrids are promising anti-tubercular molecules, which require further pre-clinical evaluation.
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28
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Stalinskaya AL, Martynenko NV, Shulgau ZT, Shustov AV, Keyer VV, Kulakov IV. Synthesis and Antiviral Properties against SARS-CoV-2 of Epoxybenzooxocino[4,3- b]Pyridine Derivatives. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123701. [PMID: 35744830 PMCID: PMC9230803 DOI: 10.3390/molecules27123701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/04/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022]
Abstract
The COVID-19 pandemic is ongoing as of mid-2022 and requires the development of new therapeutic drugs, because the existing clinically approved drugs are limited. In this work, seven derivatives of epoxybenzooxocinopyridine were synthesized and tested for the ability to inhibit the replication of the SARS-CoV-2 virus in cell cultures. Among the described compounds, six were not able to suppress the SARS-CoV-2 virus’ replication. One compound, which is a derivative of epoxybenzooxocinopyridine with an attached side group of 3,4-dihydroquinoxalin-2-one, demonstrated antiviral activity comparable to that of one pharmaceutical drug. The described compound is a prospective lead substance, because the half-maximal effective concentration is 2.23 μg/μL, which is within a pharmacologically achievable range.
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Affiliation(s)
- Alena L. Stalinskaya
- Institute of Chemistry, Tyumen State University, 15a Perekopskaya St., 625003 Tyumen, Russia; (A.L.S.); (N.V.M.)
| | - Nadezhda V. Martynenko
- Institute of Chemistry, Tyumen State University, 15a Perekopskaya St., 625003 Tyumen, Russia; (A.L.S.); (N.V.M.)
| | - Zarina T. Shulgau
- National Center for Biotechnology, 13/5 Kurgalzhynskoe road, Nur-Sultan 010000, Kazakhstan; (Z.T.S.); (A.V.S.); (V.V.K.)
| | - Alexandr V. Shustov
- National Center for Biotechnology, 13/5 Kurgalzhynskoe road, Nur-Sultan 010000, Kazakhstan; (Z.T.S.); (A.V.S.); (V.V.K.)
| | - Viktoriya V. Keyer
- National Center for Biotechnology, 13/5 Kurgalzhynskoe road, Nur-Sultan 010000, Kazakhstan; (Z.T.S.); (A.V.S.); (V.V.K.)
| | - Ivan V. Kulakov
- Institute of Chemistry, Tyumen State University, 15a Perekopskaya St., 625003 Tyumen, Russia; (A.L.S.); (N.V.M.)
- National Center for Biotechnology, 13/5 Kurgalzhynskoe road, Nur-Sultan 010000, Kazakhstan; (Z.T.S.); (A.V.S.); (V.V.K.)
- Correspondence: ; Tel.: +7-912-0775957
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29
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Prediction of drug resistance profile of multidrug-resistant Mycobacterium tuberculosis (MDR-MTB) isolates from newly diagnosed case by whole genome sequencing (WGS): a study from a high tuberculosis burden country. BMC Infect Dis 2022; 22:499. [PMID: 35624432 PMCID: PMC9137048 DOI: 10.1186/s12879-022-07482-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 05/17/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVES Our aim was to assess the ability of the Whole-genome sequencing (WGS) in predicting drug resistance profile of multidrug-resistant mycobacterium tuberculosis (MDR-MTB) from newly diagnosed cases in China. METHODS We validated the Phenotypic drug Sensitivity Test (pDST) for 12 anti-tuberculosis drugs using the Bactec MGIT 960 system. We described the characteristics of the isolates enrolled and compared the pDST results with resistance profiles predicted by WGS. RESULTS The pDST showed that of the 43 isolates enrolled, 25.6% were sensitive to rifabutin (RFB); 97.7%、97.7%、93.0% and 93.0% were sensitive to cycloserine (Cs), amikacin/kanamycin (Ak/Km), para-aminosalicylic acid (Pas) and ethionamide Eto), respectively; 18.6% were resistant to fluoroquinolones (FQs) or second-line injections. Genotype DST determined by WGS of Ak/Km、Eto and RFP reached high consistency to 97.7% compared with pDST, followed by moxifloxacin (Mfx) 95.3%, levofloxaci (Lfx) and Pas 93%, streptomycin (Sm) 90.3%. The genotype DST of RFB and EMB showed low consistency with the pDST of 67.2 and 79.1%. WGS also detected 27.9% isolates of pyrazinamide(PZA)-related drug-resistant mutation. No mutations associated with linezolid (Lzd), bedaquiline (Bdq) and clofazimine (Cfz) were detectd. CONCLUSIONS WGS has the potential to infer resistance profiles without time-consuming phenotypic methods, which could be provide a basis to formulate reasonable treatment in high TB burden areas.
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30
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Emerging impact of triazoles as anti-tubercular agent. Eur J Med Chem 2022; 238:114454. [PMID: 35597009 DOI: 10.1016/j.ejmech.2022.114454] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 05/04/2022] [Accepted: 05/08/2022] [Indexed: 01/08/2023]
Abstract
Tuberculosis, a disease of poverty is a communicable infection with a reasonably high mortality rate worldwide. 10 Million new cases of TB were reported with approx 1.4 million deaths in the year 2019. Due to the growing number of drug-sensitive and drug-resistant tuberculosis cases, there is a vital need to develop new and effective candidates useful to combat this deadly disease. Despite tremendous efforts to identify a mechanism-based novel antitubercular agent, only a few have entered into clinical trials in the last six decades. In recent years, triazoles have been well explored as the most valuable scaffolds in drug discovery and development. Triazole framework possesses favorable properties like hydrogen bonding, moderate dipole moment, enhanced water solubility, and also the ability to bind effectively with biomolecular targets of M. tuberculosis and therefore this scaffold displayed excellent potency against TB. This review is an endeavor to summarize an up-to-date innovation of triazole-appended hybrids during the last 10 years having potential in vitro and in vivo antitubercular activity with structure activity relationship analysis. This review may help medicinal chemists to explore the triazole scaffolds for the rational design of potent drug candidates having better efficacy, improved selectivity and minimal toxicity so that these hybrid NCEs can effectively be explored as potential lead to fight against M. tuberculosis.
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31
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Marquês JT, Frazão De Faria C, Reis M, Machado D, Santos S, Santos MDS, Viveiros M, Martins F, De Almeida RFM. In vitro Evaluation of Isoniazid Derivatives as Potential Agents Against Drug-Resistant Tuberculosis. Front Pharmacol 2022; 13:868545. [PMID: 35600870 PMCID: PMC9114799 DOI: 10.3389/fphar.2022.868545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/08/2022] [Indexed: 11/13/2022] Open
Abstract
The upsurge of multidrug-resistant tuberculosis has toughened the challenge to put an end to this epidemic by 2030. In 2020 the number of deaths attributed to tuberculosis increased as compared to 2019 and newly identified multidrug-resistant tuberculosis cases have been stably close to 3%. Such a context stimulated the search for new and more efficient antitubercular compounds, which culminated in the QSAR-oriented design and synthesis of a series of isoniazid derivatives active against Mycobacterium tuberculosis. From these, some prospective isonicotinoyl hydrazones and isonicotinoyl hydrazides are studied in this work. To evaluate if the chemical derivatizations are generating compounds with a good performance concerning several in vitro assays, their cytotoxicity against human liver HepG2 cells was determined and their ability to bind human serum albumin was thoroughly investigated. For the two new derivatives presented in this study, we also determined their lipophilicity and activity against both the wild type and an isoniazid-resistant strain of Mycobacterium tuberculosis carrying the most prevalent mutation on the katG gene, S315T. All compounds were less cytotoxic than many drugs in clinical use with IC50 values after a 72 h challenge always higher than 25 µM. Additionally, all isoniazid derivatives studied exhibited stronger binding to human serum albumin than isoniazid itself, with dissociation constants in the order of 10−4–10−5 M as opposed to 10−3 M, respectively. This suggests that their transport and half-life in the blood stream are likely improved when compared to the parent compound. Furthermore, our results are a strong indication that the N′ = C bond of the hydrazone derivatives of INH tested is essential for their enhanced activity against the mutant strain of M. tuberculosis in comparison to both their reduced counterparts and INH.
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Affiliation(s)
- Joaquim Trigo Marquês
- Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Catarina Frazão De Faria
- Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Marina Reis
- Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
- Instituto Superior de Educação e Ciências (ISEC Lisboa), Lisboa, Portugal
| | - Diana Machado
- Unidade de Microbiologia Medica, Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal
| | - Susana Santos
- Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Maria da Soledade Santos
- Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Miguel Viveiros
- Unidade de Microbiologia Medica, Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal
| | - Filomena Martins
- Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
- *Correspondence: Filomena Martins, ; Rodrigo F. M. De Almeida,
| | - Rodrigo F. M. De Almeida
- Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
- *Correspondence: Filomena Martins, ; Rodrigo F. M. De Almeida,
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32
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Singh Dewhare S. Drug resistant tuberculosis: Current scenario and impending challenges. Indian J Tuberc 2022; 69:227-233. [PMID: 35379406 DOI: 10.1016/j.ijtb.2021.04.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/05/2021] [Indexed: 06/14/2023]
Abstract
Tuberculosis is still one of the ten leading causes for death worldwide. In spite of the latest medical and health advance gained over a period of time, tuberculosis effectively evades the successful targeting by drugs. The persistence abilities demonstrated by the mycobacteria had surprised the global community, since its discovery and pathogenesis in humans. Emergence and detection of drug resistant mycobacteria (MDR-TB, XDR-TB) had further complicated the treatment regime. Under the aegis of WHO, there is a concerted understanding and effort by the global community to eradicate TB. Towards this goal, novel drug molecules, new vaccine and treatment regime are being developed. Here, our current understanding pertaining to mode of action, molecular mechanisms of novel as well as traditional drug molecules and possible drug resistance mechanism in M. Tuberculosis is reviewed. Recent advances on new vaccination regime are also reviewed as it demonstrated huge potential in containing TB. This knowledge is essential for the development of more effective drug molecules, vaccines and may help in devising new strategy for containing and eradicating TB.
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Affiliation(s)
- Shivendra Singh Dewhare
- School of Studies in Life Science, Pt. RavishankarShukla University, Raipur, 492010, Chhattisgarh, India.
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Characterization of pyridomycin B reveals the formation of functional groups in antimycobacterial pyridomycin. Appl Environ Microbiol 2022; 88:e0203521. [PMID: 35108072 DOI: 10.1128/aem.02035-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Pyridomycin, a cyclodepsipeptide with potent antimycobacterial activity, specifically inhibits the InhA enoyl reductase of Mycobacteria tuberculosis. Structure-activity relationship studies indicated that the enolic acid moiety in pyridomycin core system is an important pharmacophoric group and the natural configuration of the C-10 hydroxyl contributes to the bioactivity of pyridomycin. The ring structure of pyridomycin was generated by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) hybrid system (PyrE-F-G). Bioinformatics analysis reveals that SDR family protein Pyr2 functions as a 3-oxoacyl ACP reductase in the pyridomycin pathway. Inactivation of pyr2 resulted in accumulation of pyridomycin B, a new pyridomycin analogue featured with enol moiety in pyridyl alanine moiety and a saturated 3-methylvaleric acid group. The elucidated structure of pyridomycin B suggests that rather than functioning as a post-tailoring enzyme, Pyr2 catalyzes ketoreduction to form the C-10 hydroxyl group in pyridyl alanine moiety and the double bond formation of the enolic acid moiety derived from isoleucine when the intermediate assembled by PKS-NRPS machinery is still tethered to the last NRPS module, in a special energy-saving manner. Ser-His-Lys residues constitute the active site of Pyr2, which is different from the typically conserved Tyr based catalytic triad in the majority of SDRs. Site-directed mutation identified that His154 in the active site is a critical residue for pyridomycin B production. These findings will improve our understanding of the pyridomycin biosynthetic logic, identify the missing link for the double bound formation of enol ester in pyridomycin and enable creating chemical diversity of pyridomycin derivatives. Importance Tuberculosis (TB) is one of the world's leading causes of death by infection. Recently, pyridomycin, the antituberculous natural product from Streptomyces has garnered considerable attention for being determined as a target inhibitor of InhA enoyl reductase of Mycobacteria tuberculosis. In this study, we report a new pyridomycin analogue from mutant HTT12, demonstrate the essential role of a previously ignored gene pyr2 in pyridomycin biosynthetic pathway, and imply that Pyr2 functions as a trans ketoreductase (KR) contributing to the formation of functional groups of pyridomycin utilize a distinct catalytic mechanism. As enol moiety are important for pharmaceutical activities of pyridomycin, our work would expand the understanding the mechanism of SDR family proteins and set the stage for future bioengineering of new pyridomycin derivatives.
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Bendre AD, Peters PJ, Kumar J. Tuberculosis: Past, present and future of the treatment and drug discovery research. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100037. [PMID: 34909667 PMCID: PMC8663960 DOI: 10.1016/j.crphar.2021.100037] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/21/2021] [Accepted: 05/21/2021] [Indexed: 11/25/2022] Open
Abstract
Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis. Despite decades of research driving advancements in drug development and discovery against TB, it still leads among the causes of deaths due to infectious diseases. We are yet to develop an effective treatment course or a vaccine that could help us eradicate TB. Some key issues being prolonged treatment courses, inadequate drug intake, and the high dropout rate of patients during the treatment course. Hence, we require drugs that could accelerate the elimination of bacteria, shortening the treatment duration. It is high time we evaluate the probable lacunas in research holding us back in coming up with a treatment regime and/or a vaccine that would help control TB spread. Years of dedicated and focused research provide us with a lead molecule that goes through several tests, trials, and modifications to transform into a ‘drug’. The transformation from lead molecule to ‘drug’ is governed by several factors determining its success or failure. In the present review, we have discussed drugs that are part of the currently approved treatment regimen, their limitations, vaccine candidates under trials, and current issues in research that need to be addressed. While we are waiting for the path-breaking treatment for TB, these factors should be considered during the ongoing quest for novel yet effective anti-tubercular. If these issues are addressed, we could hope to develop a more effective treatment that would cure multi/extremely drug-resistant TB and help us meet the WHO's targets for controlling the global TB pandemic within the prescribed timeline.
Despite numerous drugs and vaccines undergoing clinical trials, we have not been able to control TB. Majority of articles list the advancements in the TB drug-discovery; here we review the limitations of existing treatments. Brief description of aspects to be considered for the development of one but effective drug/preventive vaccine. A glance at pediatric tuberculosis: the most neglected area of TB research which requires dedicated research efforts. A concise narrative for research aspects to be re-evaluated by both academia and pharmaceutical R&D teams.
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Key Words
- BCG, Bacille Calmette-Guérin
- BDQ, Bedaquiline
- BSL, Biosafety level
- CDC, Center for Disease Control and Prevention
- Drug discovery
- Drug resistance
- EMB, Ethambutol
- ESX, ESAT-6 secretion system
- ETC, Electron transport chain
- ETH, Ethionamide
- FAS-1, Fatty acid synthase 1
- FDA, Food and Drug Administration
- INH, Isoniazid
- LPZ, Lansoprazole
- MDR, Multidrug-resistant
- Mtb, Mycobacterium tuberculosis
- POA, pyrazinoic acid
- PZA, Pyrazinamide
- RD, the region of differences
- RIF, Rifampicin
- T7SS, Type 7 secretion system
- TB treatment
- TB, Tuberculosis
- TST, Tuberculin skin test
- Tuberculosis
- WHO, World health organization
- XDR, Extremely drug-resistant
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Affiliation(s)
- Ameya D Bendre
- Laboratory of Membrane Protein Biology, National Centre for Cell Science, NCCS Complex, S. P. Pune University, Maharashtra, Pune, 411007, India
| | - Peter J Peters
- The Maastricht Multimodal Molecular Imaging Institute (M4I), Division of Nanoscopy, Maastricht University, Maastricht, the Netherlands
| | - Janesh Kumar
- Laboratory of Membrane Protein Biology, National Centre for Cell Science, NCCS Complex, S. P. Pune University, Maharashtra, Pune, 411007, India
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Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid. Pharmaceuticals (Basel) 2021; 14:ph14121302. [PMID: 34959704 PMCID: PMC8703412 DOI: 10.3390/ph14121302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 11/17/2022] Open
Abstract
The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H37Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.125 μM), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.
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Drug Discovery for Mycobacterium tuberculosis Using Structure-Based Computer-Aided Drug Design Approach. Int J Mol Sci 2021; 22:ijms222413259. [PMID: 34948055 PMCID: PMC8703488 DOI: 10.3390/ijms222413259] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/09/2021] [Accepted: 11/14/2021] [Indexed: 12/12/2022] Open
Abstract
Developing new, more effective antibiotics against resistant Mycobacterium tuberculosis that inhibit its essential proteins is an appealing strategy for combating the global tuberculosis (TB) epidemic. Finding a compound that can target a particular cavity in a protein and interrupt its enzymatic activity is the crucial objective of drug design and discovery. Such a compound is then subjected to different tests, including clinical trials, to study its effectiveness against the pathogen in the host. In recent times, new techniques, which involve computational and analytical methods, enhanced the chances of drug development, as opposed to traditional drug design methods, which are laborious and time-consuming. The computational techniques in drug design have been improved with a new generation of software used to develop and optimize active compounds that can be used in future chemotherapeutic development to combat global tuberculosis resistance. This review provides an overview of the evolution of tuberculosis resistance, existing drug management, and the design of new anti-tuberculosis drugs developed based on the contributions of computational techniques. Also, we show an appraisal of available software and databases on computational drug design with an insight into the application of this software and databases in the development of anti-tubercular drugs. The review features a perspective involving machine learning, artificial intelligence, quantum computing, and CRISPR combination with available computational techniques as a prospective pathway to design new anti-tubercular drugs to combat resistant tuberculosis.
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Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections. Sci Rep 2021; 11:19634. [PMID: 34608194 PMCID: PMC8490354 DOI: 10.1038/s41598-021-98980-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/06/2021] [Indexed: 02/08/2023] Open
Abstract
The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide's and Fluspirilene's efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.
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Johansen MD, Shalini, Kumar S, Raynaud C, Quan DH, Britton WJ, Hansbro PM, Kumar V, Kremer L. Biological and Biochemical Evaluation of Isatin-Isoniazid Hybrids as Bactericidal Candidates against Mycobacterium tuberculosis. Antimicrob Agents Chemother 2021; 65:e0001121. [PMID: 33972252 PMCID: PMC8284457 DOI: 10.1128/aac.00011-21] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/04/2021] [Indexed: 11/20/2022] Open
Abstract
Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report here the design, synthesis, and antimycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against Mycobacterium tuberculosis, with MICs in the range of 0.195 to 0.39 μg/ml, and exerted a more potent bactericidal effect than the standard antitubercular drug isoniazid (INH). Importantly, these compounds were found to be well tolerated at high doses (>200 μg/ml) on Vero kidney cells, leading to high selectivity indices. Two of the most promising hybrids were evaluated for activity in THP-1 macrophages infected with M. tuberculosis, among which compound 11e was found to be slightly more effective than INH. Overexpression of InhA along with cross-resistance determination of the most potent compounds, selection of resistant mutants, and biochemical analysis, allowed us to decipher their mode of action. These compounds effectively inhibited mycolic acid biosynthesis and required KatG to exert their biological effects. Collectively, this suggests that the synthesized isatin-INH hybrids are promising antitubercular molecules for further evaluation in preclinical settings.
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Affiliation(s)
- Matt D. Johansen
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia
| | - Shalini
- Department of Chemistry, Guru Nanak Dev University, Punjab, India
| | - Sumit Kumar
- Department of Chemistry, Guru Nanak Dev University, Punjab, India
| | - Clément Raynaud
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France
| | - Diana H. Quan
- Tuberculosis Research Program, Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
| | - Warwick J. Britton
- Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
- Department of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Philip M. Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, NSW, Australia
| | - Vipan Kumar
- Department of Chemistry, Guru Nanak Dev University, Punjab, India
| | - Laurent Kremer
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France
- INSERM, IRIM, Montpellier, France
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Hegde P, Boshoff HIM, Rusman Y, Aragaw WW, Salomon CE, Dick T, Aldrich CC. Reinvestigation of the structure-activity relationships of isoniazid. Tuberculosis (Edinb) 2021; 129:102100. [PMID: 34116482 PMCID: PMC8324568 DOI: 10.1016/j.tube.2021.102100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/24/2021] [Accepted: 05/30/2021] [Indexed: 11/19/2022]
Abstract
Isoniazid (INH) remains a cornerstone for treatment of drug susceptible tuberculosis (TB), yet the quantitative structure-activity relationships for INH are not well documented in the literature. In this paper, we have evaluated a systematic series of INH analogs against contemporary Mycobacterium tuberculosis strains from different lineages and a few non-tuberculous mycobacteria (NTM). Deletion of the pyridyl nitrogen atom, isomerization of the pyridine nitrogen to other positions, replacement of the pyridine ring with isosteric heterocycles, and modification of the hydrazide moiety of INH abolishes antitubercular activity. Similarly, substitution of the pyridine ring at the 3-position is not tolerated while substitution at the 2-position is permitted with 2-methyl-INH 9 displaying antimycobacterial activity comparable to INH. To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of gram-positive and gram-negative bacteria, as well as a few fungi. As expected INH and its analogs display a narrow spectrum of activity and are inactive against all non-mycobacterial strains evaluated, except for 4, which has modest inhibitory activity against Cryptococcus neoformans. Our findings provide an updated analysis of the structure-activity relationship of INH that we hope will serve as useful resource for the community.
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Affiliation(s)
- Pooja Hegde
- Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Helena I M Boshoff
- Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA
| | - Yudi Rusman
- Center for Drug Design, University of Minnesota, Minneapolis, MN, 55455, USA
| | | | - Christine E Salomon
- Center for Drug Design, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Thomas Dick
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, 07110, USA
| | - Courtney C Aldrich
- Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.
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NOD: a web server to predict New use of Old Drugs to facilitate drug repurposing. Sci Rep 2021; 11:13540. [PMID: 34188160 PMCID: PMC8241987 DOI: 10.1038/s41598-021-92903-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/15/2021] [Indexed: 11/08/2022] Open
Abstract
Computational methods accelerate the drug repurposing pipelines that are a quicker and cost-effective alternative to discovering new molecules. However, there is a paucity of web servers to conduct fast, focussed, and customized investigations for identifying new uses of old drugs. We present the NOD web server, which has the mentioned characteristics. NOD uses a sensitive sequence-guided approach to identify close and distant homologs of a protein of interest. NOD then exploits this evolutionary information to suggest potential compounds from the DrugBank database that can be repurposed against the input protein. NOD also allows expansion of the chemical space of the potential candidates through similarity searches. We have validated the performance of NOD against available experimental and/or clinical reports. In 65.6% of the investigated cases in a control study, NOD is able to identify drugs more effectively than the searches made in DrugBank. NOD is freely-available at http://pauling.mbu.iisc.ac.in/NOD/NOD/ .
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Sheikh BA, Bhat BA, Mehraj U, Mir W, Hamadani S, Mir MA. Development of New Therapeutics to Meet the Current Challenge of Drug Resistant Tuberculosis. Curr Pharm Biotechnol 2021; 22:480-500. [PMID: 32600226 DOI: 10.2174/1389201021666200628021702] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/01/2020] [Accepted: 05/13/2020] [Indexed: 11/22/2022]
Abstract
Tuberculosis (TB) is a prominent infective disease and a major reason of mortality/ morbidity globally. Mycobacterium tuberculosis causes a long-lasting latent infection in a significant proportion of human population. The increasing burden of tuberculosis is mainly caused due to multi drug-resistance. The failure of conventional treatment has been observed in large number of cases. Drugs that are used to treat extensively drug-resistant tuberculosis are expensive, have limited efficacy, and have more side effects for a longer duration of time and are often associated with poor prognosis. To regulate the emergence of multidrug resistant tuberculosis, extensively drug-resistant tuberculosis and totally drug resistant tuberculosis, efforts are being made to understand the genetic/molecular basis of target drug delivery and mechanisms of drug resistance. Understanding the molecular approaches and pathology of Mycobacterium tuberculosis through whole genome sequencing may further help in the improvement of new therapeutics to meet the current challenge of global health. Understanding cellular mechanisms that trigger resistance to Mycobacterium tuberculosis infection may expose immune associates of protection, which could be an important way for vaccine development, diagnostics, and novel host-directed therapeutic strategies. The recent development of new drugs and combinational therapies for drug-resistant tuberculosis through major collaboration between industry, donors, and academia gives an improved hope to overcome the challenges in tuberculosis treatment. In this review article, an attempt was made to highlight the new developments of drug resistance to the conventional drugs and the recent progress in the development of new therapeutics for the treatment of drugresistant and non-resistant cases.
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Affiliation(s)
- Bashir A Sheikh
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Basharat A Bhat
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Umar Mehraj
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Wajahat Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Suhail Hamadani
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Manzoor A Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
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Lei S, Gu R, Ma X. Clinical perspectives of isoniazid-induced liver injury. LIVER RESEARCH 2021; 5:45-52. [PMID: 39959342 PMCID: PMC11791842 DOI: 10.1016/j.livres.2021.02.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/10/2021] [Accepted: 02/05/2021] [Indexed: 10/22/2022]
Abstract
Isoniazid (INH) is a synthetic anti-mycobacterial agent used to treat active or latent tuberculosis (TB). INH has been in clinical use for nearly 70 years and remains broadly utilized at the front line of anti-TB treatment. However, the potential for liver damage and even fulminant liver failure during INH-based TB treatment presents a major challenge for TB control programs worldwide. In this review, we discuss the hepatotoxic effects of INH and provide an overview of the mechanisms and their applications in prediction and prevention of INH hepatotoxicity in clinical practice.
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Affiliation(s)
- Saifei Lei
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ruizhi Gu
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Xiaochao Ma
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
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Subhash N, Sundaramurthy V. Advances in host-based screening for compounds with intracellular anti-mycobacterial activity. Cell Microbiol 2021; 23:e13337. [PMID: 33813790 DOI: 10.1111/cmi.13337] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 12/14/2022]
Abstract
Intracellular pathogens interact with host systems in intimate ways to sustain a pathogenic lifestyle. Consequently, these interactions can potentially be targets of host-directed interventions against infectious diseases. In case of tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), while effective anti-tubercular compounds are available, the long treatment duration and emerging drug resistance necessitate identification of new class of molecules with anti-TB activity, as well as new treatment strategies. A significant part of the effort in finding new anti-TB drugs is focused on bacterial targets in bacterial systems. However, the host environment plays a major role in pathogenesis mechanisms and must be considered actively in these efforts. On the one hand, the bacterial origin targets must be relevant and accessible in the host, while on the other hand, new host origin targets required for the bacterial survival can be targeted. Such targets are good candidates for host-directed therapeutics, a strategy gaining traction as an adjunct in TB treatment. In this review, we will summarise the screening platforms used to identify compounds with anti-tubercular activities inside different host environments and outline recent technical advances in these platforms. Finally, while the examples given are specific to mycobacteria, the methods and principles outlined are broadly applicable to most intracellular infections.
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Affiliation(s)
- Neeraja Subhash
- National Center for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India.,SASTRA University, Thanjavur, India
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Yuan T, Werman JM, Sampson NS. The pursuit of mechanism of action: uncovering drug complexity in TB drug discovery. RSC Chem Biol 2021; 2:423-440. [PMID: 33928253 PMCID: PMC8081351 DOI: 10.1039/d0cb00226g] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 12/23/2020] [Indexed: 12/21/2022] Open
Abstract
Whole cell-based phenotypic screens have become the primary mode of hit generation in tuberculosis (TB) drug discovery during the last two decades. Different drug screening models have been developed to mirror the complexity of TB disease in the laboratory. As these culture conditions are becoming more and more sophisticated, unraveling the drug target and the identification of the mechanism of action (MOA) of compounds of interest have additionally become more challenging. A good understanding of MOA is essential for the successful delivery of drug candidates for TB treatment due to the high level of complexity in the interactions between Mycobacterium tuberculosis (Mtb) and the TB drug used to treat the disease. There is no single "standard" protocol to follow and no single approach that is sufficient to fully investigate how a drug restrains Mtb. However, with the recent advancements in -omics technologies, there are multiple strategies that have been developed generally in the field of drug discovery that have been adapted to comprehensively characterize the MOAs of TB drugs in the laboratory. These approaches have led to the successful development of preclinical TB drug candidates, and to a better understanding of the pathogenesis of Mtb infection. In this review, we describe a plethora of efforts based upon genetic, metabolomic, biochemical, and computational approaches to investigate TB drug MOAs. We assess these different platforms for their strengths and limitations in TB drug MOA elucidation in the context of Mtb pathogenesis. With an emphasis on the essentiality of MOA identification, we outline the unmet needs in delivering TB drug candidates and provide direction for further TB drug discovery.
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Affiliation(s)
- Tianao Yuan
- Department of Chemistry, Stony Brook UniversityStony BrookNY 11794-3400USA+1-631-632-5738+1-631-632-7952
| | - Joshua M. Werman
- Department of Chemistry, Stony Brook UniversityStony BrookNY 11794-3400USA+1-631-632-5738+1-631-632-7952
| | - Nicole S. Sampson
- Department of Chemistry, Stony Brook UniversityStony BrookNY 11794-3400USA+1-631-632-5738+1-631-632-7952
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Strategies for drug target identification in Mycobacterium leprae. Drug Discov Today 2021; 26:1569-1573. [PMID: 33798649 DOI: 10.1016/j.drudis.2021.03.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/01/2021] [Accepted: 03/23/2021] [Indexed: 11/22/2022]
Abstract
Hansen's disease (HD), or leprosy, continues to be endemic in many parts of the world. Although multidrug therapy (MDT) is successful in curing a large number of patients, some of them abandon it because it is a long-term treatment. Therefore, identification of new drug targets in Mycobacterium leprae is considered of high importance. Here, we introduce an overview of in silico and in vitro studies that might be of help in this endeavor. The essentiality of M. leprae proteins is reviewed with discussion of flux balance analysis, gene expression, and knockout articles. Finally, druggability techniques are proposed for the validation of new M. leprae protein targets (see Fig. 1).
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Rohde KH, Sorci L. The Prospective Synergy of Antitubercular Drugs With NAD Biosynthesis Inhibitors. Front Microbiol 2021; 11:634640. [PMID: 33584600 PMCID: PMC7873932 DOI: 10.3389/fmicb.2020.634640] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 12/23/2020] [Indexed: 11/29/2022] Open
Abstract
Given the upsurge of drug-resistant tuberculosis worldwide, there is much focus on developing novel drug combinations allowing shorter treatment duration and a lower toxicity profile. Nicotinamide adenine dinucleotide (NAD) biosynthesis targeting is acknowledged as a promising strategy to combat drug-susceptible, drug-resistant, and latent tuberculosis (TB) infections. In this review, we describe the potential synergy of NAD biosynthesis inhibitors with several TB-drugs in prospective novel combination therapy. Despite not directly targeting the essential NAD cofactor's biosynthesis, several TB prodrugs either require a NAD biosynthesis enzyme to be activated or form a toxic chemical adduct with NAD(H) itself. For example, pyrazinamide requires the action of nicotinamidase (PncA), often referred to as pyrazinamidase, to be converted into its active form. PncA is an essential player in NAD salvage and recycling. Since most pyrazinamide-resistant strains are PncA-defective, a combination with downstream NAD-blocking molecules may enhance pyrazinamide activity and possibly overcome the resistance mechanism. Isoniazid, ethionamide, and delamanid form NAD adducts in their active form, partly perturbing the redox cofactor metabolism. Indeed, NAD depletion has been observed in Mycobacterium tuberculosis (Mtb) during isoniazid treatment, and activation of the intracellular NAD phosphorylase MbcT toxin potentiates its effect. Due to the NAD cofactor's crucial role in cellular energy production, additional synergistic correlations of NAD biosynthesis blockade can be envisioned with bedaquiline and other drugs targeting energy-metabolism in mycobacteria. In conclusion, future strategies targeting NAD metabolism in Mtb should consider its potential synergy with current and other forthcoming TB-drugs.
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Affiliation(s)
- Kyle H. Rohde
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Leonardo Sorci
- Division of Bioinformatics and Biochemistry, Department of Materials, Environmental Sciences and Urban Planning, Polytechnic University of Marche, Ancona, Italy
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Kumar CBP, Raghu MS, Prasad KNN, Chandrasekhar S, Jayanna BK, Alharthi FA, Prashanth MK, Kumar KY. Investigation of biological activity of 2,3-disubstituted quinazolin-4(1H)-ones against Mycobacterium tuberculosis and DNA via docking, spectroscopy and DFT studies. NEW J CHEM 2021. [DOI: 10.1039/d0nj03800h] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Docking studies, structural data of DNA binding and molecular dynamics simulations of substituted quinazolin-4(1H)-ones.
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Affiliation(s)
| | - M. S. Raghu
- Department of Chemistry
- New Horizon College of Engineering
- Bengaluru 560 103
- India
| | - K. N. N. Prasad
- Department of Physics
- B N M Institute of Technology
- Bengaluru-560 070
- India
| | - S. Chandrasekhar
- Department of Physics
- B N M Institute of Technology
- Bengaluru-560 070
- India
| | - B. K. Jayanna
- Department of Chemistry
- B N M Institute of Technology
- Bengaluru-560 070
- India
| | - Fahad A. Alharthi
- Department of Chemistry
- College of Science
- King Saud University
- Riyadh
- Saudi Arabia
| | - M. K. Prashanth
- Department of Chemistry
- B N M Institute of Technology
- Bengaluru-560 070
- India
| | - K. Yogesh Kumar
- Department of Chemistry
- School of Engineering and Technology
- Jain University
- Ramanagara
- India
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Różycka D, Korycka-Machała M, Żaczek A, Dziadek J, Gurda D, Orlicka-Płocka M, Wyszko E, Biniek-Antosiak K, Rypniewski W, Olejniczak AB. Novel Isoniazid-Carborane Hybrids Active in Vitro Against Mycobacterium tuberculosis. Pharmaceuticals (Basel) 2020; 13:ph13120465. [PMID: 33333865 PMCID: PMC7765321 DOI: 10.3390/ph13120465] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/27/2020] [Accepted: 12/11/2020] [Indexed: 12/11/2022] Open
Abstract
Tuberculosis (TB) is a severe infectious disease with high mortality and morbidity. The emergence of drug-resistant TB has increased the challenge to eliminate this disease. Isoniazid (INH) remains the key and effective component in the therapeutic regimen recommended by World Health Organization (WHO). A series of isoniazid-carborane derivatives containing 1,2-dicarba-closo-dodecaborane, 1,7-dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane, or 7,8-dicarba-nido-undecaborate anion were synthesized for the first time. The compounds were tested in vitro against the Mycobacterium tuberculosis (Mtb) H37Rv strain and its mutant (DkatG) defective in the synthesis of catalase-peroxidase (KatG). N'-((7,8-dicarba-nido-undecaboranyl)methylidene)isonicotinohydrazide (16) showed the highest activity against the wild-type Mtb strain. All hybrids could inhibit the growth of the ΔkatG mutant in lower concentrations than INH. N'-([(1,12-dicarba-closo-dodecaboran-1yl)ethyl)isonicotinohydrazide (25) exhibited more than 60-fold increase in activity against Mtb DkatG as compared to INH. This compound was also found to be noncytotoxic up to a concentration four times higher than the minimum inhibitory concentration 99% (MIC99) value.
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Affiliation(s)
- Daria Różycka
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa St., 93-232 Lodz, Poland; (D.R.); (M.K.-M.); (J.D.)
| | - Małgorzata Korycka-Machała
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa St., 93-232 Lodz, Poland; (D.R.); (M.K.-M.); (J.D.)
| | - Anna Żaczek
- Institute of Medical Sciences, Medical College, University of Rzeszow, 2A Kopisto Avenue, 35-959 Rzeszow, Poland;
| | - Jarosław Dziadek
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa St., 93-232 Lodz, Poland; (D.R.); (M.K.-M.); (J.D.)
| | - Dorota Gurda
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 12/14Z. Noskowskiego St., 61-704 Poznan, Poland; (D.G.); (M.O.-P.); (E.W.); (K.B.-A.); (W.R.)
| | - Marta Orlicka-Płocka
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 12/14Z. Noskowskiego St., 61-704 Poznan, Poland; (D.G.); (M.O.-P.); (E.W.); (K.B.-A.); (W.R.)
| | - Eliza Wyszko
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 12/14Z. Noskowskiego St., 61-704 Poznan, Poland; (D.G.); (M.O.-P.); (E.W.); (K.B.-A.); (W.R.)
| | - Katarzyna Biniek-Antosiak
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 12/14Z. Noskowskiego St., 61-704 Poznan, Poland; (D.G.); (M.O.-P.); (E.W.); (K.B.-A.); (W.R.)
| | - Wojciech Rypniewski
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 12/14Z. Noskowskiego St., 61-704 Poznan, Poland; (D.G.); (M.O.-P.); (E.W.); (K.B.-A.); (W.R.)
| | - Agnieszka B. Olejniczak
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa St., 93-232 Lodz, Poland; (D.R.); (M.K.-M.); (J.D.)
- Correspondence: ; Tel.: +48-42-272-36-37
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Alghamdi S, Rehman SU, Shesha NT, Faidah H, Khurram M, Rehman SU. Promising Lead Compounds in the Development of Potential Clinical Drug Candidate for Drug-Resistant Tuberculosis. Molecules 2020; 25:molecules25235685. [PMID: 33276545 PMCID: PMC7729780 DOI: 10.3390/molecules25235685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/26/2020] [Accepted: 12/01/2020] [Indexed: 11/16/2022] Open
Abstract
According to WHO report, globally about 10 million active tuberculosis cases, resulting in about 1.6 million deaths, further aggravated by drug-resistant tuberculosis and/or comorbidities with HIV and diabetes are present. Incomplete therapeutic regimen, meager dosing, and the capability of the latent and/or active state tubercular bacilli to abide and do survive against contemporary first-line and second line antitubercular drugs escalate the prevalence of drug-resistant tuberculosis. As a better understanding of tuberculosis, microanatomy has discovered an extended range of new promising antitubercular targets and diagnostic biomarkers. However, there are still no new approved antitubercular drugs of routine therapy for several decades, except for bedaquiline, delamanid, and pretomanid approved tentatively. Despite this, innovative methods are also urgently needed to find potential new antitubercular drug candidates, which potentially decimate both latent state and active state mycobacterium tuberculosis. To explore and identify the most potential antitubercular drug candidate among various reported compounds, we focused to highlight the promising lead derivatives of isoniazid, coumarin, griselimycin, and the antimicrobial peptides. The aim of the present review is to fascinate significant lead compounds in the development of potential clinical drug candidates that might be more precise and effective against drug-resistant tuberculosis, the world research looking for a long time.
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Affiliation(s)
- Saad Alghamdi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Mecca 24321, Saudi Arabia;
| | - Shaheed Ur Rehman
- Department of Pharmacy, Abasyn University Peshawar, Khyber Pakhtunkhwa 25000, Pakistan;
- Correspondence: (S.U.R.); (M.K.); Tel.: +923459832402 (S.U.R.)
| | - Nashwa Talaat Shesha
- Regional Laboratory, Directorate of Health Affairs Makkah, Mecca 24321, Saudi Arabia;
| | - Hani Faidah
- Microbiology Department, Faculty of Medicine, Umm Al-Qura University, Mecca 24321, Saudi Arabia;
| | - Muhammad Khurram
- Department of Pharmacy, Abasyn University Peshawar, Khyber Pakhtunkhwa 25000, Pakistan;
- Correspondence: (S.U.R.); (M.K.); Tel.: +923459832402 (S.U.R.)
| | - Sabi Ur Rehman
- Department of Pharmacy, Abasyn University Peshawar, Khyber Pakhtunkhwa 25000, Pakistan;
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Mukhtar M, Pallagi E, Csóka I, Benke E, Farkas Á, Zeeshan M, Burián K, Kókai D, Ambrus R. Aerodynamic properties and in silico deposition of isoniazid loaded chitosan/thiolated chitosan and hyaluronic acid hybrid nanoplex DPIs as a potential TB treatment. Int J Biol Macromol 2020; 165:3007-3019. [DOI: 10.1016/j.ijbiomac.2020.10.192] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 10/16/2020] [Accepted: 10/24/2020] [Indexed: 12/21/2022]
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