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Current Opinion in Microbiology Oct 2022Tuberculosis (TB) persists as a major global health issue and a leading cause of death by a single infectious agent. The global burden of TB is further exacerbated by... (Review)
Review
Tuberculosis (TB) persists as a major global health issue and a leading cause of death by a single infectious agent. The global burden of TB is further exacerbated by the continuing emergence and dissemination of strains of Mycobacterium tuberculosis resistant to multiple antibiotics. The need for novel drugs that can be used to shorten the course for current TB drug regimens as well as combat the persistent threat of antibiotic resistance has never been greater. There have been significant advances in the discovery of de novo TB treatments, with the first TB-specific drugs in 45 years approved for use. However, there are still issues that restrict the pipeline of new antitubercular chemotherapies. The rate of failure of TB drug candidates in clinical trials remains high, while the validation of new TB drug targets and subsequent identification of novel inhibitors remains modest.
Topics: Antitubercular Agents; Drug Delivery Systems; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 35970040
DOI: 10.1016/j.mib.2022.102191 -
The Journal of Antimicrobial... Feb 2012Clofazimine, a lipophilic riminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities. However, its efficacy has been demonstrated only... (Review)
Review
Clofazimine, a lipophilic riminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities. However, its efficacy has been demonstrated only in the treatment of leprosy, not in human tuberculosis, despite the fact that this agent is impressively active in vitro against multidrug-resistant strains of Mycobacterium tuberculosis. Recent insights into novel targets and mechanisms of antimicrobial and anti-inflammatory activity coupled with the acquisition of innovative drug delivery technologies have, however, rekindled interest in clofazimine as a potential therapy for multidrug- and extensively multidrug-resistant tuberculosis in particular, as well as several autoimmune diseases. The primary objective of this review is to critically evaluate these recent developments and to assess their potential impact on improving the therapeutic efficacy and versatility of clofazimine.
Topics: Anti-Inflammatory Agents; Antitubercular Agents; Clofazimine; Drug Resistance, Multiple, Bacterial; Humans; Leprosy; Mycobacterium tuberculosis; Tuberculosis
PubMed: 22020137
DOI: 10.1093/jac/dkr444 -
Scientific Reports May 2023There exists decades-old evidence that some mycobacteria, including Mycobacterium avium and Mycobacterium smegmatis, produce hydrazidase, an enzyme that can hydrolyze...
There exists decades-old evidence that some mycobacteria, including Mycobacterium avium and Mycobacterium smegmatis, produce hydrazidase, an enzyme that can hydrolyze the first-line antitubercular agent isoniazid. Despite its importance as a potential resistance factor, no studies have attempted to reveal its identity. In this study, we aimed to isolate and identify M. smegmatis hydrazidase, characterize it, and evaluate its impact on isoniazid resistance. We determined the optimal condition under which M. smegmatis produced the highest amount of hydrazidase, purified the enzyme by column chromatography, and identified it by peptide mass fingerprinting. It was revealed to be PzaA, an enzyme known as pyrazinamidase/nicotinamidase whose physiological role remains unknown. The kinetic constants suggested that this amidase with broad substrate specificity prefers amides to hydrazides as a substrate. Notably, of the five tested compounds, including amides, only isoniazid served as an efficient inducer of pzaA transcription, as revealed by quantitative reverse transcription PCR. Moreover, high expression of PzaA was confirmed to be beneficial for the survival and growth of M. smegmatis in the presence of isoniazid. Thus, our findings suggest a possible role for PzaA, and other hydrazidases yet to be identified, as an intrinsic isoniazid resistance factor of mycobacteria.
Topics: Isoniazid; Mycobacterium; Antitubercular Agents; Mycobacterium smegmatis; Amides; Mycobacterium tuberculosis
PubMed: 37210419
DOI: 10.1038/s41598-023-35213-5 -
Cell Mar 2023The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called...
The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.
Topics: Animals; Mice; Antitubercular Agents; Macrolides; Drug Resistance, Bacterial; Mycobacterium tuberculosis; Clarithromycin
PubMed: 36827973
DOI: 10.1016/j.cell.2023.01.043 -
Nature Reviews. Chemistry May 2023Drug metabolism is generally associated with liver enzymes. However, in the case of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB),... (Review)
Review
Drug metabolism is generally associated with liver enzymes. However, in the case of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), Mtb-mediated drug metabolism plays a significant role in treatment outcomes. Mtb is equipped with enzymes that catalyse biotransformation reactions on xenobiotics with consequences either in its favour or as a hindrance by deactivating or activating chemical entities, respectively. Considering the range of chemical reactions involved in the biosynthetic pathways of Mtb, information related to the biotransformation of antitubercular compounds would provide opportunities for the development of new chemical tools to study successful TB infections while also highlighting potential areas for drug discovery, host-directed therapy, dose optimization and elucidation of mechanisms of action. In this Review, we discuss Mtb-mediated biotransformations and propose a holistic approach to address drug metabolism in TB drug discovery and related areas.
Topics: Humans; Mycobacterium tuberculosis; Xenobiotics; Antitubercular Agents; Tuberculosis; Latent Tuberculosis
PubMed: 37117810
DOI: 10.1038/s41570-023-00472-3 -
Duodecim; Laaketieteellinen... 2014The causative agent of MDR tuberculosis is resistant to at least isoniazid and rifampin, and in the case of XDR tuberculosis, also to fluoroquinolones and... (Review)
Review
The causative agent of MDR tuberculosis is resistant to at least isoniazid and rifampin, and in the case of XDR tuberculosis, also to fluoroquinolones and aminoglycoside. In 2012, 450000 people had MDR tuberculosis and 170000 people died of it. The majority of the cases were reported in South Africa, India, and Russia. In North West Russia nearly one third of the new tuberculosis cases are MDR. In Finland 2-5 new cases of MDR tuberculosis are notified annually, and this far only one case of XDR tuberculosis has been reported. Treatment of MDR tuberculosis lasts longer and costs more than treatment of drug-susceptible tuberculosis. Moreover, the second line drugs used are less effective and have more side effects than the first line drugs.
Topics: Antitubercular Agents; Global Health; Humans; Population Surveillance; Tuberculosis, Multidrug-Resistant
PubMed: 25269365
DOI: No ID Found -
Cellular and Molecular Life Sciences :... Sep 2023Lipid species play a critical role in the growth and virulence expression of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). During Mtb... (Review)
Review
Lipid species play a critical role in the growth and virulence expression of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). During Mtb infection, foamy macrophages accumulate lipids in granulomas, providing metabolic adaptation and survival strategies for Mtb against multiple stresses. Host-derived lipid species, including triacylglycerol and cholesterol, can also contribute to the development of drug-tolerant Mtb, leading to reduced efficacy of antibiotics targeting the bacterial cell wall or transcription. Transcriptional and metabolic analyses indicate that lipid metabolism-associated factors of Mtb are highly regulated by antibiotics and ultimately affect treatment outcomes. Despite the well-known association between major antibiotics and lipid metabolites in TB treatment, a comprehensive understanding of how altered lipid metabolites in both host and Mtb influence treatment outcomes in a drug-specific manner is necessary to overcome drug tolerance. The current review explores the controversies and correlations between lipids and drug efficacy in various Mtb infection models and proposes novel approaches to enhance the efficacy of anti-TB drugs. Moreover, the review provides insights into the efficacious control of Mtb infection by elucidating the impact of lipids on drug efficacy. This review aims to improve the effectiveness of current anti-TB drugs and facilitate the development of innovative therapeutic strategies against Mtb infection by making reverse use of Mtb-favoring lipid species.
Topics: Humans; Lipid Metabolism; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis; Triglycerides
PubMed: 37704889
DOI: 10.1007/s00018-023-04914-5 -
The Journal of Infectious Diseases Nov 2023Mycobacterium tuberculosis, the causative agent of tuberculosis, is acquiring drug resistance at a faster rate than the discovery of new antibiotics. Therefore,...
Mycobacterium tuberculosis, the causative agent of tuberculosis, is acquiring drug resistance at a faster rate than the discovery of new antibiotics. Therefore, alternate therapies that can limit the drug resistance and disease recurrence are urgently needed. Emerging evidence indicates that combined treatment with antibiotics and an immunomodulator provides superior treatment efficacy. Clofazimine (CFZ) enhances the generation of T central memory (TCM) cells by blocking the Kv1.3+ potassium channels. Rapamycin (RAPA) facilitates M. tuberculosis clearance by inducing autophagy. In this study, we observed that cotreatment with CFZ and RAPA potently eliminates both multiple and extensively drug-resistant (MDR and XDR) clinical isolates of M. tuberculosis in a mouse model by inducing robust T-cell memory and polyfunctional TCM responses. Furthermore, cotreatment reduces the expression of latency-associated genes of M. tuberculosis in human macrophages. Therefore, CFZ and RAPA cotherapy holds promise for treating patients infected with MDR and XDR strains of M. tuberculosis.
Topics: Animals; Mice; Humans; Clofazimine; Antitubercular Agents; Sirolimus; Memory T Cells; Tuberculosis, Multidrug-Resistant; Mycobacterium tuberculosis; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 37290049
DOI: 10.1093/infdis/jiad214 -
Current Medicinal Chemistry 2014ATP: shikimate 3-phosphotransferase catalyzes the fifth chemical reaction of shikimate pathway. This metabolic route is responsible for the production of chorismate, a... (Review)
Review
ATP: shikimate 3-phosphotransferase catalyzes the fifth chemical reaction of shikimate pathway. This metabolic route is responsible for the production of chorismate, a precursor of aromatic amino acids. This especially interesting enzymatic step is indispensable for the survival of the etiological agent of tuberculosis and not found in animals. Therefore the enzyme ATP: shikimate 3-phosphotransferase has been classified as a target for chemotherapeutic development of antitubercular drugs. The ATP:shikimate 3-phosphotransferase has also the denomination of shikimate kinase. This review highlights the available crystallographic studies of shikimate kinases that have been used to identify structural features for ligand-biding affinity. We also describe molecular docking studies focused on shikimate kinase. These computational studies were performed in order to identify the new generation of antitubercular drugs and several potential inhibitors have been described. In addition, a structural comparison of shikimate kinase ATP-binding pocket with human cyclin-dependent kinase 2 (CDK2) is described. This analysis shows the structural similarities between both enzymes, and the potential beneficial aspects of abundant structural studies of CDK2 and their inhibitors to bring further understanding of the ligand-binding specificity for shikimate kinase.
Topics: Antitubercular Agents; Bacterial Proteins; Binding Sites; Catalytic Domain; Cyclin-Dependent Kinase 2; Drug Design; Humans; Ligands; Molecular Docking Simulation; Mycobacterium tuberculosis; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 24164195
DOI: 10.2174/09298673113206660299 -
The Indian Journal of Tuberculosis Oct 2022Multi-drug resistance tuberculosis is chronic and highly affected to mankind. Millions of people are affected by tuberculosis and lost their lives every year....
BACKGROUND
Multi-drug resistance tuberculosis is chronic and highly affected to mankind. Millions of people are affected by tuberculosis and lost their lives every year. Mycobacterium tuberculosis is resistant to the most commonly used anti-TB drugs, hence new drugs need to be developed in a short time. In this direction, many chemical compounds including benzimidazole derivatives have been identified as potent anti-tb agents.
METHOD
Various benzimidazole derivatives were subjected to in-silico computational screening to identify the potent anti-tubercular analogues. The ADME pharmacokinetics evaluation was performed to identify the drug-like molecules. Molecular docking investigation of selected compounds was performed against Mycobacterium Tuberculosis Enoyl Reductase (Inha) with PDB ID: 2B37, 1QG6, 4TZK, and 4TZK. The common pharmacophore hypothesis was generated using the molecular docking post-processing module.
RESULT
The result of ADME pharmacokinetics of some compounds is very close to the drug-like properties and can be developed as good inhibitors. Molecular docking study suggests that the proposed benzimidazole and 4H-pyran derivative have better binding affinity than standard and triclosan derivatives. Results from the pharmacophore hypothesis development study also support and suggest our prediction regarding the minimum pharmacophore features required in ligands to behave as a Mycobacterium Tuberculosis inhibitor.
CONCLUSION
Coumarin, phenylurea clubbed benzimidazole moiety and pyrano[2,3-c]pyrazole derivatives have shown greater selectivity and potency towards Mycobacterium Tuberculosis. By employing a combination of ADME, docking, and pharmacophore study calculations, novel potent hits to inhibit enoyl-acp reductase were identified with the points for consideration for designing of enoyl-acp reductase inhibitor.
Topics: Humans; Antitubercular Agents; Molecular Docking Simulation; Mycobacterium tuberculosis; Tuberculosis, Lymph Node; Benzimidazoles; Oxidoreductases
PubMed: 36460382
DOI: 10.1016/j.ijtb.2021.08.014