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Pharmacotherapy Nov 2014Bedaquiline is a diarylquinoline antitubercular drug with a novel mechanism of action against Mycobacterium tuberculosis. Bedaquiline works by inhibiting bacterial... (Review)
Review
Bedaquiline is a diarylquinoline antitubercular drug with a novel mechanism of action against Mycobacterium tuberculosis. Bedaquiline works by inhibiting bacterial adenosine triphosphate (ATP) synthase and represents the first novel class of antituberculosis agents in more than 40 years. Bedaquiline is indicated for the treatment of multidrug-resistant tuberculosis (MDR TB) in combination with at least three other antitubercular drugs when no other effective regimen is available. The recommended bedaquiline dosage is 400 mg orally once/day for 2 weeks followed by 200 mg orally 3 times/week for 22 weeks. Bedaquiline should be administered with food, which increases the bioavailability 2-fold. Bedaquiline is metabolized by cytochrome P450 isoenzyme 3A4 and is impacted by both inducers and inhibitors of this isoenzyme. Concentration-dependent bactericidal activity was observed in laboratory and murine studies. Accelerated approval was granted in the United States and European Union based on the results of two phase IIb clinical studies that used sputum culture clearance as a surrogate end point for clinical efficacy. These studies showed greater sputum culture clearance up to week 24 for the bedaquiline group compared with placebo. Common adverse events in clinical trials included nausea, arthralgia, and headache. Serious adverse events included elevated serum transaminase levels and rate-corrected QT-interval prolongation. Unexplained higher mortality was seen in patients receiving bedaquiline versus those receiving placebo. Bedaquiline is a novel agent with a unique mechanism of action and has the potential to meet a great need in patients with MDR TB who have no other treatment options. Due to safety concerns and limited clinical information, phase III trials are needed to fully determine its place in therapy.
Topics: ATP Synthetase Complexes; Animals; Antitubercular Agents; Bacterial Proteins; Bacterial Proton-Translocating ATPases; Diarylquinolines; Drug Interactions; Drugs, Investigational; Enzyme Inhibitors; Humans; Mycobacterium tuberculosis; Practice Guidelines as Topic; Tuberculosis, Multidrug-Resistant
PubMed: 25203970
DOI: 10.1002/phar.1482 -
Archiv Der Pharmazie Oct 2021Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library...
Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library of 3-aryl-substituted imidazo[1,2-a]pyridines was synthesized using direct arylation, followed by nitro reduction and finally Pd-catalyzed C-N coupling reactions. The compounds thus obtained were evaluated against Mycobacterium tuberculosis H37Rv. Compound 26 was identified as an antituberculosis lead with a minimum inhibitory concentration of 2.3 μg/ml against M. tuberculosis H37Rv. This compound showed a selectivity index of 35. The docking of 26 in the active site of the M. tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π-π interactions of compound 26 with the Tyr389 and Trp312 residues of Mtb QcrB.
Topics: Antitubercular Agents; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Pyridines; Structure-Activity Relationship
PubMed: 34185337
DOI: 10.1002/ardp.202000419 -
Frontiers in Cellular and Infection... 2020(), the causative agent of tuberculosis (TB), remains the leading cause of death from an infectious bacterium and is responsible for 1.8 million deaths annually. The... (Review)
Review
(), the causative agent of tuberculosis (TB), remains the leading cause of death from an infectious bacterium and is responsible for 1.8 million deaths annually. The emergence of drug resistance, together with the need for a shorter more effective regimen, has prompted the drive to identify novel therapeutics with the bacterial cell surface emerging as a tractable area for drug development. assembles a unique, waxy, and complex cell envelope comprised of the mycolyl-arabinogalactan-peptidoglycan complex and an outer capsule like layer, which are collectively essential for growth and pathogenicity while serving as an inherent barrier against antibiotics. A detailed understanding of the biosynthetic pathways required to assemble the polymers that comprise the cell surface will enable the identification of novel drug targets as these structures provide a diversity of biochemical reactions that can be targeted. Herein, we provide an overview of recently described mycobacterial cell wall targeting compounds, novel drug combinations and their modes of action. We anticipate that this summary will enable prioritization of the best pathways to target and triage of the most promising molecules to progress for clinical assessment.
Topics: Antitubercular Agents; Cell Wall; Drug Delivery Systems; Humans; Mycobacterium tuberculosis; Pharmaceutical Preparations; Tuberculosis
PubMed: 33282752
DOI: 10.3389/fcimb.2020.603382 -
Microbiology Spectrum Oct 2016The tuberculosis agent Mycobacterium tuberculosis has undergone a long and selective evolution toward human infection and represents one of the most widely spread... (Review)
Review
The tuberculosis agent Mycobacterium tuberculosis has undergone a long and selective evolution toward human infection and represents one of the most widely spread pathogens due to its efficient aerosol-mediated human-to-human transmission. With the availability of more and more genome sequences, the evolutionary trajectory of this obligate pathogen becomes visible, which provides us with new insights into the molecular events governing evolution of the bacterium and its ability to accumulate drug-resistance mutations. In this review, we summarize recent developments in mycobacterial research related to this matter that are important for a better understanding of the current situation and future trends and developments in the global epidemiology of tuberculosis, as well as for possible public health intervention possibilities.
Topics: Animals; Antitubercular Agents; Drug Resistance; Evolution, Molecular; Genome, Bacterial; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 27787194
DOI: 10.1128/microbiolspec.TBTB2-0020-2016 -
Medicinal Research Reviews Mar 2018Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and... (Review)
Review
Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold-containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti-TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti-TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references.
Topics: Animals; Antitubercular Agents; Biomedical Research; Humans; Tuberculosis
PubMed: 28598559
DOI: 10.1002/med.21454 -
Recent Advances in Anti-infective Drug... 2022Chemical modification of Oxadiazole may lead to a potent therapeutic agent. A series of novel 5-pyrazyl-2-sulfanyl-1, 3, 4-oxadiazole derivatives (5ag) have been...
BACKGROUND
Chemical modification of Oxadiazole may lead to a potent therapeutic agent. A series of novel 5-pyrazyl-2-sulfanyl-1, 3, 4-oxadiazole derivatives (5ag) have been synthesised utilising pyrazinoic acid as a precursor. The new oxadiazole compounds were docked against potential targets and evaluated for antibacterial and antitubercular activity.
METHODS
The 5-pyrazyl-2-substituted sulfanyl-1, 3,4-oxadiazole derivatives (5a-g) were synthesized from the crucial intermediate 2-sulfanyl-5-pyrazyl-1, 3,4-oxadiazole (4), which was prepared by treating the 2-pyrazyl hydrazide with CS2 and pyridine. IR, HNMR, C, MS and elemental analyses were used to confirm the chemical structures.
RESULTS
Antimicrobial activity was determined for each synthesized compound. Additionally, compounds were evaluated for antitubercular activity against the Mycobacterium Tuberculosis H37Rv strain. Compounds 5c, 5g, and 5a had a favourable antibacterial profile, while 5c and 5g (MIC = 25 g/ml) demonstrated potential antitubercular activity when compared to the other produced compounds. Molecular docking experiments using V-Life Science MDS 4.6 supplemented the biological data.
CONCLUSION
Each compound has been tested for antibacterial and antitubercular action against a variety of microorganism strains and exhibits considerable activity. Additionally, molecular docking analysis confirmed the experimental results by describing improved interaction patterns.
Topics: Oxadiazoles; Molecular Docking Simulation; Structure-Activity Relationship; Antitubercular Agents; Mycobacterium tuberculosis
PubMed: 35692159
DOI: 10.2174/2772434417666220609105755 -
Chemical Reviews Feb 2018Current tuberculosis (TB) drug development efforts are not sufficient to end the global TB epidemic. Recent efforts have focused on the development of whole-cell... (Review)
Review
Current tuberculosis (TB) drug development efforts are not sufficient to end the global TB epidemic. Recent efforts have focused on the development of whole-cell screening assays because biochemical, target-based inhibitor screens during the last two decades have not delivered new TB drugs. Mycobacterium tuberculosis (Mtb), the causative agent of TB, encounters diverse microenvironments and can be found in a variety of metabolic states in the human host. Due to the complexity and heterogeneity of Mtb infection, no single model can fully recapitulate the in vivo conditions in which Mtb is found in TB patients, and there is no single "standard" screening condition to generate hit compounds for TB drug development. However, current screening assays have become more sophisticated as researchers attempt to mirror the complexity of TB disease in the laboratory. In this review, we describe efforts using surrogates and engineered strains of Mtb to focus screens on specific targets. We explain model culture systems ranging from carbon starvation to hypoxia, and combinations thereof, designed to represent the microenvironment which Mtb encounters in the human body. We outline ongoing efforts to model Mtb infection in the lung granuloma. We assess these different models, their ability to generate hit compounds, and needs for further TB drug development, to provide direction for future TB drug discovery.
Topics: Antitubercular Agents; Drug Discovery; Genome, Human; Granuloma; Humans; Mycobacterium tuberculosis
PubMed: 29384369
DOI: 10.1021/acs.chemrev.7b00602 -
Expert Review of Anti-infective Therapy Oct 2016Linezolid is an oxazolidinone with potent activity against M tuberculosis, and improves culture conversion and cure rates when added to treatment regimens for drug... (Review)
Review
INTRODUCTION
Linezolid is an oxazolidinone with potent activity against M tuberculosis, and improves culture conversion and cure rates when added to treatment regimens for drug resistant tuberculosis. However, linezolid has a narrow therapeutic window, and the optimal dosing strategy that minimizes the substantial toxicity associated with linezolid's prolonged use in tuberculosis treatment has not been determined, limiting the potential impact of this anti-mycobacterial agent.
AREAS COVERED
This paper aims to review and summarize the current knowledge on linezolid for the treatment of drug-resistant tuberculosis. The focus is on the pharmacokinetic-pharmacodynamic determinants of linezolid's efficacy and toxicity in tuberculosis, and how this relates to defining an optimal dose. Mechanisms of linezolid toxicity and resistance, and the potential role of therapeutic drug monitoring are also covered. Expert commentary: Prospective pharmacokinetic-pharmacodynamic studies are required to define optimal therapeutic targets and to inform improved linezolid dosing strategies for drug-resistant tuberculosis.
Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Humans; Linezolid; Mitochondria; Mycobacterium tuberculosis; Practice Guidelines as Topic; Protein Binding; Toxicogenetics; Tuberculosis, Multidrug-Resistant
PubMed: 27532292
DOI: 10.1080/14787210.2016.1225498 -
Oxidative Medicine and Cellular... 2018Tuberculosis (TB), caused by the bacterium , is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols... (Review)
Review
Tuberculosis (TB), caused by the bacterium , is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB; this commonly manifests as multidrug resistant tuberculosis (MDR-TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first-/second-line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, -oxidation) and pathogen (catalase/peroxidase enzyme, EthA). Additionally, has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of to counter the host's OS response.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Lung; Mycobacterium tuberculosis; Oxidative Stress; Tuberculosis
PubMed: 30405878
DOI: 10.1155/2018/7695364 -
The Lancet. Microbe Feb 2023
Topics: Mycobacterium tuberculosis; Antitubercular Agents; Ethambutol; Microbial Sensitivity Tests
PubMed: 36354021
DOI: 10.1016/S2666-5247(22)00299-3