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Bioorganic & Medicinal Chemistry Letters Feb 2019The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a...
The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019-0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC = 40->120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.
Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Female; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Nitrofurans; Vero Cells
PubMed: 30600207
DOI: 10.1016/j.bmcl.2018.12.053 -
Current Opinion in Microbiology Oct 2014Reactive multi-target fragments, old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like,... (Review)
Review
Reactive multi-target fragments, old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules, represent critical components of current tuberculosis chemotherapies. Recent studies showed that para-aminosalicylic acid is recognized as a substrate by dihydropteroate synthase and poisons the downstream folate pathway. Pyrazinamide, a key relapse-reducing drug, is metabolized by an amidase and the reaction product interferes with trans-translation, membrane potential and other targets. However, the mechanism of action of pyrazinamide remains ill-defined and needs to be understood to rationally approach treatment shortening. The success of small dirty drugs and prodrugs suggests that fragment-based whole cell screens should be re-introduced in our current antimycobacterial drug discovery efforts.
Topics: Antitubercular Agents; Drug Discovery; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis
PubMed: 25078318
DOI: 10.1016/j.mib.2014.06.015 -
Journal of Biomolecular Structure &... Mar 2022Tuberculosis (TB) has been recently declared as a health emergency because of sporadic increase in Multidrug-resistant Tuberculosis (MDR-TB) problem throughout the...
Tuberculosis (TB) has been recently declared as a health emergency because of sporadic increase in Multidrug-resistant Tuberculosis (MDR-TB) problem throughout the world. TB causing bacteria, has become resistant to the first line of treatment along with second line of treatment and drugs, which are accessible to us. Thus, there is an urgent need of identification of key targets and development of potential therapeutic approach(s), which can overcome the complications. In the present study, proteasome has been taken as a potential target as it is one of the key regulatory proteins in propagation. Further, a library of 400 compounds (small molecule) from Medicines for Malaria Venture (MMV) were screened against the target (proteasome) using molecular docking and simulation approach, and selected lead compounds were validated in model. In this study, we have identified two potent small molecules from the MMV Pathogen Box library, MMV019838 and MMV687146 with -9.8kcal/mol and -8.7kcal/mol binding energy respectively, which actively interact with the catalytic domain/active domain of proteasome and inhibit the growth in culture. Furthermore, the molecular docking and simulation study of MMV019838 and MMV687146 with proteasome show strong and stable interaction with compared to human proteasome and show no cytotoxicity effect. A better understanding of proteasome inhibition in in and model would eventually allow us to understand the molecular mechanism(s) and discover a novel and potent therapeutic agent against Tuberculosis. Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. Efflux pump activity was tested for a specific compound MMV019838 which was showing good in silico results than MIC values.Communicated by Ramaswamy H. Sarma.
Topics: Antitubercular Agents; Humans; Molecular Docking Simulation; Mycobacterium tuberculosis; Proteasome Inhibitors; Tuberculosis, Multidrug-Resistant
PubMed: 33074049
DOI: 10.1080/07391102.2020.1835722 -
Biomedicine & Pharmacotherapy =... Jun 2023Tuberculosis (TB) maintains its infamous status regarding its detrimental effect on global health, causing the highest mortality by a single infectious agent. The... (Review)
Review
Tuberculosis (TB) maintains its infamous status regarding its detrimental effect on global health, causing the highest mortality by a single infectious agent. The presence of resistance and immune compromising disease favours the disease in maintaining its footing in the health care burden despite various anti-TB drugs used to fight it. Main factors contributing to resistance and difficulty in treating disease include prolonged treatment duration (at least 6 months) and severe toxicity, which further leads to patient non-compliance, and thus a ripple effect leading to therapeutic non-efficacy. The efficacy of new regimens demonstrates that targeting host factors concomitantly with the Mycobacterium tuberculosis (M.tb) strain is urgently required. Due to the huge expenses and time required of up to 20 years for new drug research and development, drug repurposing may be the most economical, circumspective, and conveniently faster journey to embark on. Host-directed therapy (HDT) will dampen the burden of the disease by acting as an immunomodulator, allowing it to defend the body against antibiotic-resistant pathogens whilst minimizing the possibility of developing new resistance to susceptible drugs. Repurposed drugs in TB act as host-directed therapies, acclimatizing the host immune cell to the presence of TB, improving its antimicrobial activity and time taken to get rid of the disease, whilst minimizing inflammation and tissue damage. In this review, we, therefore, explore possible immunomodulatory targets, HDT immunomodulatory agents, and their ability to improve clinical outcomes whilst minimizing the risk of drug resistance, through various pathway targeting and treatment duration reduction.
Topics: Humans; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis; Immunologic Factors; Adjuvants, Immunologic
PubMed: 36989709
DOI: 10.1016/j.biopha.2023.114588 -
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 -
Journal of Tropical Pediatrics Aug 2015Pellagra is a disorder characterized by dermatitis, diarrhea, dementia and eventually death, resulting from a deficiency of niacin or its precursor tryptophan....
Pellagra is a disorder characterized by dermatitis, diarrhea, dementia and eventually death, resulting from a deficiency of niacin or its precursor tryptophan. Ethionamide (a second-line antituberculosis agent)-induced pellagra is rarely encountered in clinical practice. Prompt diagnosis and treatment with nicotinamide can prevent life-threatening complications. To date, only three cases have been reported. We report a 13-year-old girl presenting with ethionamide-induced pellagra that resolved after the administration of niacin.
Topics: Adolescent; Antitubercular Agents; Diagnosis, Differential; Ethionamide; Female; Humans; Niacin; Pellagra; Treatment Outcome; Tuberculosis, Pulmonary
PubMed: 25828829
DOI: 10.1093/tropej/fmv021 -
The International Journal of... Aug 2021National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia. To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with...
National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia. To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with an intensified regimen including a fluoroquinolone (FQ) and an injectable agent. Prospective cohort of patients aged ≥16 years initiating treatment for TBM at the NCTLD from January 2018 to December 2019. Treatment outcomes and neurologic disability at 1, 6 and 12 months after treatment initiation were assessed. Among 77 patients with median follow-up time of 363 days (IQR 269-374), 97% received a FQ, 62% an injectable agent, 44% linezolid and 39% a carbapenem. Fifty-seven patients (74%) successfully completed treatment, 2 (2.6%) had treatment failure, 6 (7.8%) died, and the remainder (12%) were lost to follow up. Among 11 patients treated for multidrug-resistant TBM, the median follow-up time was 467 days and one patient (8%) died. Regarding neurologic outcomes, 14/76 (18%) patients had Modified Rankin Scores of 0 at baseline, improving to 85% (56/66) and 94% (47/50) at 6 and 12 months, respectively. Intensified multidrug treatment regimens including a FQ and an injectable agent in all patients and newly implemented drugs in patients with multidrug-resistant TBM resulted in low mortality and favorable neurologic outcomes.
Topics: Antitubercular Agents; Fluoroquinolones; Humans; Linezolid; Prospective Studies; Tuberculosis, Meningeal
PubMed: 34330348
DOI: 10.5588/ijtld.21.0159 -
European Journal of Drug Metabolism and... Jan 2021The objectives of this qualitative review were to critically evaluate and summarize the currently available data on the use of anti-tuberculosis (TB) drugs during... (Review)
Review
The objectives of this qualitative review were to critically evaluate and summarize the currently available data on the use of anti-tuberculosis (TB) drugs during pregnancy, with a focus on treatment outcomes, safety, and pharmacokinetics. This qualitative, narrative review was based on literature searches in Medline, Pubmed, Embase, and Google Scholar (from their inception to 13 August 2020). Our search identified 22 papers related to treatment outcomes and 14 papers related to pharmacokinetic exposures and fetal distributions. While it is challenging to study this patient population, current evidence supports treatment of drug-susceptible TB, multidrug-resistant TB and latent TB infections. However, decisions regarding initiating, continuing, or discontinuing anti-tubercular medications while pregnant should be individualized and discussed with a specialist. Similarly, the pharmacokinetic data of anti-TB agents were mainly derived from small scale, observational studies many of which lacked high quality controls. Based on these data, it does not appear that pregnancy has an extensive impact on the pharmacokinetics of the majority of first-line and second-line agents, although caution (discussed in the review) should be exercised in data interpretation. Fetal drug exposure can also be significant and should be considered when selecting an anti-TB agent for longer term treatment. Overall, it is generally difficult to predict pregnancy-associated pharmacokinetic changes based only on drug's physiochemical characteristics.
Topics: Antitubercular Agents; Female; Humans; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Retrospective Studies; Tuberculosis, Multidrug-Resistant
PubMed: 33206364
DOI: 10.1007/s13318-020-00657-x -
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 -
Current Topics in Medicinal Chemistry 2021Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent, mainly due to Mycobacterium tuberculosis... (Review)
Review
Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent, mainly due to Mycobacterium tuberculosis (MTB). Recently, clinical prognoses have worsened due to the emergence of multi-drug resistant (MDR) and extensive-drug resistant (XDR) tuberculosis, which lead to the need for new, efficient and safe drugs. Among the several strategies, polypharmacology could be considered one of the best solutions, in particular, the multitarget directed ligands strategy (MTDLs), based on the synthesis of hybrid ligands acting against two targets of the pathogen. The framework strategy comprises linking, fusing and merging approaches to develop new chemical entities. With these premises, this review aims to provide an overview of the recent hybridization approach, in medicinal chemistry, of the most recent and promising multitargeting antimycobacterial candidates.
Topics: Antitubercular Agents; Drug Discovery; Humans; Mycobacterium tuberculosis; Nucleic Acid Hybridization
PubMed: 32814528
DOI: 10.2174/1568026620666200819151342