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The Annals of Pharmacotherapy Jan 2014To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and administration of bedaquiline, a novel... (Review)
Review
OBJECTIVE
To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and administration of bedaquiline, a novel oral diarylquinoline antimycobacterial agent approved by the Food and Drug Administration for the treatment of adults with pulmonary multidrug-resistant tuberculosis (MDR-TB).
DATA SOURCES
A search of PubMed (January 2004-May 2013) and International Pharmaceutical Abstracts (January 2004-May 2013) using the search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included proceedings of the Union World Conference on Lung Health.
STUDY SELECTION AND DATA EXTRACTION
Preclinical data as well as Phase 1 and 2 studies published in English were evaluated.
DATA SYNTHESIS
Bedaquiline possesses a unique mechanism of action that disrupts the activity of the mycobacterial adenosine triphosphate synthase. Clinical trials have been conducted evaluating the use of bedaquiline in combination with a background regimen for the treatment of adults with pulmonary MDR-TB. Bedaquiline has an excellent in vitro activity against Mycobacterium tuberculosis, including multidrug resistant M tuberculosis; however, its side effect profile limits its use against MDR-TB when no other effective regimen can be provided. Bedaquiline carries Black Box warnings for increased risk of unexplained mortality and QT prolongation. Bedaquiline is metabolized via the CYP3A4 isoenzyme and thus interacts with rifamycins and several antiretrovirals.
CONCLUSIONS
In an era of emerging resistance and given the suboptimal efficacy and toxicity of currently available regimens for MDR-TB, bedaquiline represents a great addition to the existing armamentarium of anti-TB agents particularly in areas of the world where the disease is endemic.
Topics: Animals; Antitubercular Agents; Diarylquinolines; Drug Interactions; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 24259600
DOI: 10.1177/1060028013504087 -
Mini Reviews in Medicinal Chemistry 2022Tuberculosis (TB) is an acute or chronic infectious disease caused by several species of Mycobacterium, collectively called tubercle bacilli or Mycobacterium... (Review)
Review
BACKGROUND
Tuberculosis (TB) is an acute or chronic infectious disease caused by several species of Mycobacterium, collectively called tubercle bacilli or Mycobacterium tuberculosis complex. Around 10 million people get sick with tuberculosis (TB) each year. TB is the second leading cause of death today after HIV/AIDS. A serious problem in the context of MDR-TB is the extensively drug-resistant TB, which is an important reason for the restricted chemotherapy in TB. Therefore, there is a need to explore new antitubercular (anti-TB) agents. Coumarin is an oxygencontaining heterocyclic compound and can be widely found in many natural products, and many of them display diverse biological activities. The wide spectrum of activities of coumarin molecules has intrigued the scientists to explore the natural coumarins and their synthetic derivatives for their potential as anti-TB drugs.
OBJECTIVE
The objective of this review is to emphasize important coumarin analogs with anti-TB activities and their structure-activity relationships (SAR) for designing better anti-TB agents.
METHOD
Latest, authentic and published reports on various synthetic and natural coumarin derivatives and their anti-TB activities is being thoroughly studied and analyzed. The structural requirements of coumarins as anti-TB drugs have also been studied.
RESULT
Collection and compilation of reports on various synthetic and natural coumarin derivatives and their anti-TB activities are being performed.
CONCLUSION
The study provides the latest report on coumarin derivatives synthesized as anti-TB agent and whether their activity depends on structural changes or not.
Topics: Antitubercular Agents; Coumarins; Drug Design; Extensively Drug-Resistant Tuberculosis; Humans; Mycobacterium tuberculosis
PubMed: 34579635
DOI: 10.2174/1389557521666210927124511 -
The European Respiratory Journal Jul 2021Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for...
Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from Tuberculosis Trials Consortium (TBTC) studies 27 and 28 and Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) multi-arm multi-stage tuberculosis (MAMS-TB), multi-centre phase 2 trials in which participants received rifampicin (range 10-35 mg·kg), pyrazinamide (range 20-30 mg·kg), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK-PD) and pharmacokinetic-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (C) was associated with shorter time to culture conversion (TTCC) and higher probability of 2-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide C increased and varied by rifampicin area under the curve (p-value<0.01). Modelling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with grade 3 or higher liver function tests (LFT)), and no relationship was seen between pyrazinamide C and LFT levels.Pyrazinamide's microbiological efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel.
Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis
PubMed: 33542052
DOI: 10.1183/13993003.02013-2020 -
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 -
Molecules (Basel, Switzerland) Oct 2022We evaluated the anti-mycobacterial effect of a flavonoid 5,7-dihydroxy-2-(4-hydroxyphenyl) 4-chromen-4-one () and two pyrimidines,...
We evaluated the anti-mycobacterial effect of a flavonoid 5,7-dihydroxy-2-(4-hydroxyphenyl) 4-chromen-4-one () and two pyrimidines, 4-hydroxy-2-dimethylamino-5-nitroso-6-aminopyrimidine () and 2-chloro-5--nonylpyrimidine () in vitro against (, H37Ra) and , using a Microplate Alamar Blue Assay (MABA). The effects of the compounds - in combination with first- and second-line anti-TB drugs isoniazid, rifampicin, cycloserine, and clarithromycin on the growth of and were also evaluated in in vitro assays. As a single agent, compounds and exhibited modest activity while compound was the most effective against and . When compounds - were evaluated at lower than 50% of their inhibitory concentrations in a two-drug combination with isoniazid or rifampicin, they showed additive to synergistic interactions. This inhibitory effect was improved when each of the three compounds was tested together in a three-drug combination with two of the first-line anti-TB drugs. Compounds - also demonstrated strong synergistic interaction in combination with cycloserine and clarithromycin in inhibiting the growth of and , respectively. This study demonstrated that compounds - have potential to be developed as effective anti-TB agents with combined use.
Topics: Antitubercular Agents; Clarithromycin; Cycloserine; Drug Combinations; Flavonoids; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium tuberculosis; Pyrimidines; Rifampin; Tuberculosis
PubMed: 36235249
DOI: 10.3390/molecules27196714 -
Current Medicinal Chemistry 2012Isocitrate lyase plays a key role for survival of Mycobacterium tuberculosis in the latent form during a chronic stage of infection. This enzyme is important for M.... (Review)
Review
Isocitrate lyase plays a key role for survival of Mycobacterium tuberculosis in the latent form during a chronic stage of infection. This enzyme is important for M. tuberculosis during steady stage growth when it converts isocitrate to succinate and glyoxylate. Then, the glyoxylate is condensed with acetyl-CoA to form malate by malate synthase. The carbon conserving glyoxylate pathway has not been observed in mammals; therefore, it has been determined as a potential drug target for discovery of a new antituberculosis agent. Novel active molecules should shorten the duration of therapy, prevent resistance development and eliminate latent disease. The review summarizes recent progresses in isocitrate lyase inhibitors, overviews structural analogues of several metabolic intermediates (3-nitropropionate, 3-bromopyruvate, itaconate, itaconic anhydride), peptide inhibitors, and recently developed inhibitors with various chemical structures. The largest inhibitory activity against isocitrate lyase (IC(50) of 0.10 ± 0.01 μM) and concomitantly a significant antimycobacterial activity has been presented by fluoroquinolone derivative 1-cyclopropyl-7-[3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which has incorporated 3-nitropropionyl group as one of the structural analogue of succinate, a metabolic intermediate.
Topics: Antitubercular Agents; Bacterial Proteins; Enzyme Inhibitors; Fluoroquinolones; Isocitrate Lyase; Mycobacterium tuberculosis; Nucleotides; Peptides; Protein Binding
PubMed: 23092127
DOI: 10.2174/092986712804485782 -
The Lancet. Infectious Diseases Jul 2022Tuberculosis is second only to COVID-19 as a cause of death from a single infectious agent. In 2020, almost 10 million people were estimated to have developed... (Review)
Review
Tuberculosis is second only to COVID-19 as a cause of death from a single infectious agent. In 2020, almost 10 million people were estimated to have developed tuberculosis and it caused 1·5 million deaths. Around a quarter of deaths caused by antimicrobial resistance are due to rifampicin-resistant tuberculosis. Antimicrobial resistance surveillance systems for many bacterial pathogens are still in the early stages of implementation in many countries, and do not yet allow for the estimation of disease burden at the national level. In this Personal View, we present the achievements, challenges, and way forward for the oldest and largest global antimicrobial resistance surveillance system. Hosted by WHO since 1994, the Global Project on Anti-Tuberculosis Drug Resistance Surveillance has served as a platform for the evaluation of the trends in anti-tuberculosis drug resistance for over 25 years at country, regional, and global levels. With an estimated 465 000 incident cases of multidrug-resistant and rifampicin-resistant tuberculosis in 2019, drug-resistant tuberculosis remains a public health crisis. The COVID-19 pandemic has reversed years of progress in providing essential tuberculosis services and reducing disease burden. The number of people diagnosed with drug-resistant tuberculosis has dropped by 22% since before the pandemic, and the number of patients provided with treatment for drug-resistant tuberculosis has dropped by 15%. Now more than ever, closing gaps in the detection of drug-resistant tuberculosis requires investment in research and development of new diagnostic tools and their rollout, expansion of sample transport systems, and the implementation of data connectivity solutions.
Topics: Antitubercular Agents; COVID-19; Humans; Mycobacterium tuberculosis; Pandemics; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 35248168
DOI: 10.1016/S1473-3099(21)00808-2 -
Molecules (Basel, Switzerland) Mar 2020According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people...
According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino--phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against H37Ra and four other mycobacterial strains (, , , ) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, -(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)--(-tolyl)pyrazine-2-carboxamide (, MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the genus.
Topics: Antitubercular Agents; Drug Design; Drug Development; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Pyrazines; Structure-Activity Relationship
PubMed: 32231166
DOI: 10.3390/molecules25071561 -
The Journal of Antimicrobial... Nov 2011The objective of the present study was to evaluate the antitubercular activity of amino and acyl amino derivatives of coumarins when used alone and in combination with...
OBJECTIVES
The objective of the present study was to evaluate the antitubercular activity of amino and acyl amino derivatives of coumarins when used alone and in combination with isoniazid, rifampicin, streptomycin or ethambutol, and to decipher the mode of action of the most effective agent.
METHODS
A series of amino and acyl amino coumarins were synthesized and screened for activity against the Mycobacterium tuberculosis H37Rv strain. These compounds were further evaluated by standard assay procedures to determine their MBCs, fractional inhibitory concentration index values and cytotoxicities. The MICs for a susceptible and a multidrug-resistant clinical isolate of M. tuberculosis were also determined. Electron and fluorescence microscopy of the test compound-treated mycobacterial samples were also carried out in an attempt to find out the target of action.
RESULTS
7-Amino-4-methylcoumarin (7-amino-4-methyl-2H-chromen-2-one; NA5) displayed the lowest MIC of 1 mg/L against not only H37Rv but also the susceptible as well as the multidrug-resistant clinical isolates. Certain acyl amino coumarins were also found to inhibit the aforementioned strains and isolates with MICs in the range of 1.0-3.5 mg/L. They were also found to act in synergy with isoniazid/rifampicin. Electron microscopy revealed the cell-wall-attacking characteristic of these compounds, while fluorescence microscopy indicated that mycolic acid might be the target of action.
CONCLUSIONS
The present study clearly demonstrated the in vitro antitubercular potential of the novel drug candidate NA5. Further studies are warranted to establish the in vivo efficacy and therapeutic potential of NA5.
Topics: Antitubercular Agents; Cell Wall; Coumarins; Drug Resistance, Multiple, Bacterial; Drug Synergism; Ethambutol; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycolic Acids; Rifampin; Streptomycin; Structure-Activity Relationship
PubMed: 21917615
DOI: 10.1093/jac/dkr355 -
Antimicrobial Agents and Chemotherapy Nov 2023BTZ-043, a suicide inhibitor of the cell wall synthesis decaprenylphosphoryl-beta-D-ribose 2' epimerase, is under clinical development as a potential new...
BTZ-043, a suicide inhibitor of the cell wall synthesis decaprenylphosphoryl-beta-D-ribose 2' epimerase, is under clinical development as a potential new anti-tuberculosis agent. BTZ-043 is potent and bactericidal but has limited activity against non-growing bacilli in rabbit caseum. To better understand its behavior , BTZ-043 was evaluated for efficacy and spatial drug distribution as a single agent in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon infection. BTZ-043 promoted significant reductions in lung and spleen bacterial burdens in the C3HeB/FeJ mouse model after 2 months of therapy. BTZ-043 penetrates cellular and necrotic lesions and was retained at levels above the serum-shifted minimal inhibitory concentration in caseum. The calculated rate of kill was found to be highest and dose-dependent during the second month of treatment. BTZ-043 treatment was associated with improved histology scores of pulmonary lesions, especially compared to control mice, which experienced advanced fulminant neutrophilic alveolitis in the absence of treatment. These positive treatment responses to BTZ-043 monotherapy in a mouse model of advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in the caseum, and its high potency and bactericidal nature at drug concentrations achieved in necrotic lesions.
Topics: Humans; Mice; Animals; Rabbits; Mice, Inbred C3H; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis; Mice, Inbred Strains
PubMed: 37791784
DOI: 10.1128/aac.00597-23