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Accounts of Chemical Research Aug 2019Tuberculosis (TB) is the leading cause of mortality globally resulting from an infectious disease, killing almost 1.6 million people annually and accounting for... (Review)
Review
Tuberculosis (TB) is the leading cause of mortality globally resulting from an infectious disease, killing almost 1.6 million people annually and accounting for approximately 30% of deaths attributed to antimicrobial resistance (AMR). This despite the widespread administration of a neonatal vaccine, and the availability of an effective combination drug therapy against the causative agent, (Mtb). Instead, TB prevalence worldwide is characterized by high-burden regions in which co-epidemics, such as HIV, and social and economic factors, undermine efforts to control TB. These elements additionally ensure conditions that favor the emergence of drug-resistant Mtb strains, which further threaten prospects for future TB control. To address this challenge, significant resources have been invested in developing a TB drug pipeline, an initiative given impetus by the recent regulatory approval of two new anti-TB drugs. However, both drugs have been reserved for drug-resistant disease, and the seeming inevitability of new resistance plus the recognized need to shorten the duration of chemotherapy demands continual replenishment of the pipeline with high-quality "hits" with novel mechanisms of action. This represents a massive challenge, which has been undermined by key gaps in our understanding of Mtb physiology and metabolism, especially during host infection. Whereas drug discovery for other bacterial infections can rely on predictive in vitro assays and animal models, for Mtb, inherent metabolic flexibility and uncertainties about the nutrients available to infecting bacilli in different host (micro)environments instead requires educated predictions or demonstrations of efficacy in animal models of arguable relevance to human disease. Even microbiological methods for enumeration of viable mycobacterial cells are fraught with complication. Our research has focused on elucidating those aspects of mycobacterial metabolism that contribute to the robustness of the bacillus to host immunological defenses and applied antibiotics and that, possibly, drive the emergence of drug resistance. This work has identified a handful of metabolic pathways that appear vulnerable to antibiotic targeting. Those highlighted, here, include the inter-related functions of pantothenate and coenzyme A biosynthesis and recycling and nucleotide metabolism-the last of which reinforces our view that DNA metabolism constitutes an under-explored area for new TB drug development. Although nonessential functions have traditionally been deprioritized for antibiotic development, a common theme emerging from this work is that these very functions might represent attractive targets because of the potential to cripple mechanisms critical to bacillary survival under stress (for example, the Rel-dependent stringent response) or to adaptability under unfavorable, potentially lethal, conditions including antibiotic therapy (for example, DnaE2-dependent SOS mutagenesis). The bar, however, is high: demonstrating convincingly the likely efficacy of this strategy will require innovative models of human TB disease. In the concluding section, we focus on the need for improved techniques to elucidate mycobacterial metabolism during infection and its impact on disease outcomes. Here, we argue that developments in other fields suggest the potential to break through this barrier by harnessing chemical-biology approaches in tandem with the most advanced technologies. As researchers based in a high-burden country, we are impelled to continue participating in this important endeavor.
Topics: Animals; Antitubercular Agents; Drug Discovery; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 31361123
DOI: 10.1021/acs.accounts.9b00275 -
The International Journal of... Nov 2016Carbapenems, a more recent β-lactam class, represent a unique anti-tuberculosis option, as emerging evidence demonstrates that they target the Mycobacterium... (Review)
Review
Carbapenems, a more recent β-lactam class, represent a unique anti-tuberculosis option, as emerging evidence demonstrates that they target the Mycobacterium tuberculosis cell wall and β-lactamase. This provides a potentially new agent against M. tuberculosis, in particular for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), where options are limited. In this review, we examine the current evidence on the activity of carbapenems against M. tuberculosis. The predominance of work is in vitro, and suggests that carbapenems kill M. tuberculosis at least in the active phase, with possible greater potency with the addition of a β-lactamase inhibitor. The few in vivo and clinical studies suggest that there are benefits and that they are generally tolerated, although the variability in duration, dosing, and background regimen and lack of pharmacokinetic analyses limit interpretation of efficacy. We outline further areas of research to better understand the role of carbapenems to add a needed new agent to the treatment of MDR- and XDR-TB.
Topics: Animals; Antitubercular Agents; Carbapenems; Cell Wall; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Extensively Drug-Resistant Tuberculosis; Humans; Incidence; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prevalence; Randomized Controlled Trials as Topic; beta-Lactamases
PubMed: 27776583
DOI: 10.5588/ijtld.16.0498 -
Trends in Microbiology Jan 2022Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis, was the leading cause of mortality worldwide in 2019 due to a single... (Review)
Review
Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis, was the leading cause of mortality worldwide in 2019 due to a single infectious agent. The growing threat of strains of M. tuberculosis untreatable by modern antibiotic regimens only exacerbates this problem. In response to this continued public health emergency, research into methods of potentiating currently approved antimicrobial agents against resistant strains of M. tuberculosis is an urgent priority, and a key strategy in this regard is the design of mycobacterial efflux pump inhibitors (EPIs). This review summarises the current state of knowledge surrounding drug-related efflux pumps in M. tuberculosis and presents recent updates within the field of mycobacterial EPIs with a view to aiding the design of an effective adjunct therapy to overcome efflux-mediated resistance in TB.
Topics: Anti-Infective Agents; Antitubercular Agents; Bacterial Proteins; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 34052094
DOI: 10.1016/j.tim.2021.05.001 -
Current Opinion in Pharmacology Oct 2018Tuberculosis now ranks as the leading cause of death in the world due to a single infectious agent. Current standard of care treatment can achieve very high cure rates... (Review)
Review
Tuberculosis now ranks as the leading cause of death in the world due to a single infectious agent. Current standard of care treatment can achieve very high cure rates for drug-sensitive disease but requires a 6-month duration of chemotherapy. Drug-resistant disease requires significantly longer treatment durations with drugs associated with a higher risk of adverse events. Thus, there is a pressing need for a drug regimen that is safer, shorter in duration and superior to current front-line chemotherapy in terms of efficacy. The TB drug pipeline contains several candidates that address one or more of the required attributes of chemotherapeutic regimens that may redefine the standard of care of this disease. Several new drugs have been reported and novel targets have been identified allowing regimens containing new compounds to trickle into clinical studies. Furthermore, a recent paradigm-shift in understanding the pharmacokinetics of anti-tubercular drugs is revolutionizing the way we select compounds for clinical progression.
Topics: Animals; Antitubercular Agents; Drug Development; Drug Resistance; Drug Therapy, Combination; Humans; Tuberculosis
PubMed: 30144650
DOI: 10.1016/j.coph.2018.08.001 -
Future Medicinal Chemistry Mar 2019In recent times, heterocyclic chemotypes are being explored for the development of new antimycobacterials that target the drug-resistant tuberculosis. Here, we are...
AIM
In recent times, heterocyclic chemotypes are being explored for the development of new antimycobacterials that target the drug-resistant tuberculosis. Here, we are disclosing the 5-substitued 2-mercapto-1,3,4-oxadiazoles as potent antitubercular agents.
METHODOLOGY
A small library of 2-mercapto-1,3,4-oxadiazoles was synthesized using various acids. The compounds were evaluated for antituberculosis activity against M. tuberculosis H37Rv.
RESULTS
Compound 8j was identified as antitubercular lead with MIC of 0.6 μg/ml against M. tuberculosis H37Rv. This compound was nontoxic to CHO-K1 cells and showed selectivity index of 39. Of note, 8j showed antitubercular activity against pre-extensively drug-resistant clinical isolate of Mycobacterium with MIC of 2 μg/ml.
CONCLUSION
This study provides potent antitubercular agent which can be further optimized to discover novel antibiotics.
Topics: Antitubercular Agents; Cell Line; Humans; Models, Molecular; Mycobacterium tuberculosis; Oxadiazoles; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 30892944
DOI: 10.4155/fmc-2018-0378 -
The FEBS Journal Jul 2022Epigenetics involves changing the gene function without any change in the sequence of the genes. In the case of tuberculosis (TB) infections, the bacilli, Mycobacterium... (Review)
Review
Epigenetics involves changing the gene function without any change in the sequence of the genes. In the case of tuberculosis (TB) infections, the bacilli, Mycobacterium tuberculosis (M.tb), uses epigenetics as a tool to protect itself from the host immune system. TB is a deadly disease-causing maximum death per year due to a single infectious agent. In the case of TB, there is an urgent need for novel host-directed therapies which can effectively target the survival and long-term persistence of the bacteria without developing drug resistance in the bacterial strains while also reducing the duration and toxicity associated with the mainstream anti-TB drugs. Recent studies have suggested that TB infection has a significant effect on the host epigenome thereby manipulating the host immune response in the favor of the pathogen. M.tb alters the activation status of key genes involved in the immune response against TB to promote its survival and subvert the antibacterial strategies of the host. These changes are reversible and can be exploited to design very efficient host-directed therapies to fight against TB. This review has been written with the purpose of discussing the role of epigenetic changes in TB pathogenesis and the therapeutic approaches involving epigenetics, which can be utilized for targeting the pathogen.
Topics: Antitubercular Agents; Epigenesis, Genetic; Epigenomics; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 34453865
DOI: 10.1111/febs.16170 -
Bioorganic & Medicinal Chemistry Letters Nov 2020In a search of new antitubercular agents, herein we have reported a series of new thirty-two indanol-1,2,3-triazole derivatives. The synthesized compounds were screened...
In a search of new antitubercular agents, herein we have reported a series of new thirty-two indanol-1,2,3-triazole derivatives. The synthesized compounds were screened for their in vitro antitubercular and antimicrobial activities. Among the screened compounds, most of the compounds have displayed good antitubercular activity against Mycobacterium tuberculosis H37Rv. The compound 5g has been identified as potent antitubercular agent with MIC value 1.56 µM. The most active compounds of the series were further studied for their cytotoxicity against HEK 293 cells using MTT assay and found to be nontoxic. In addition, ten compounds were shown good antimicrobial activities against both antibacterial and antifungal pathogens. A molecular docking study against Mycobacterial enoyl-ACP-reductase (InhA) was performed to gain an insight into the molecular mechanism of antitubercular action. The pharmacokinetic parameters of these compounds were studied and displayed acceptable drug-likeness score.
Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Drug Design; HEK293 Cells; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Triazoles
PubMed: 32987135
DOI: 10.1016/j.bmcl.2020.127579 -
European Journal of Medicinal Chemistry Apr 2017In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily...
In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily accessible compounds possessed high in vitro antimycobacterial activities against Mycobacterium tuberculosis, including clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with submicromolar minimum inhibitory concentrations (MICs). The most promising compounds showed low in vitro cytotoxicity and negligible antibacterial and antifungal activities, highlighting their highly selective antimycobacterial effects. 2-Substituted 5-(3,5-dinitrophenyl)-2H-tetrazole regioisomers, which are the dominant products of 5-(3,5-dinitrophenyl)-1H-tetrazole alkylation, showed better properties with respect to antimycobacterial activity and cytotoxicity than their 1-substituted counterparts. The 2-substituent of 5-(3,5-dinitrophenyl)-2H-tetrazole can be easily modified and can thus be used for the structure optimization of these promising antitubercular agents. The introduction of a tetrazole-5-thioalkyl moiety at position 2 of the tetrazole further increased the antimycobacterial activity. These compounds showed outstanding in vitro activity against M. tuberculosis (MIC values as low as 0.03 μM) and high activity against non-tuberculous mycobacterial strains.
Topics: Antitubercular Agents; Drug Resistance, Multiple; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Species Specificity; Structure-Activity Relationship; Tetrazoles
PubMed: 28279848
DOI: 10.1016/j.ejmech.2017.02.058 -
ChemMedChem Mar 20228-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two...
8-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds' antimycobacterial properties are described. Reactions of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one and the clinical drug candidate BTZ043 with the Grignard reagent CH MgBr afford the corresponding dearomatized stable 4,5-dimethyl-5H- and 4,7-dimethyl-7H-benzo[e][1,3]thiazines. These methine compounds are structurally characterized by X-ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non-planar 4H-benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH ) S ⋅ BH . Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis, as proven by in vitro growth inhibition assays.
Topics: Antitubercular Agents; Crystallography, X-Ray; Mycobacterium smegmatis; Mycobacterium tuberculosis; Thiazines
PubMed: 35170242
DOI: 10.1002/cmdc.202200021 -
Molecules (Basel, Switzerland) Jan 2019has recently surpassed HIV/AIDS as the leading cause of death by a single infectious agent. The standard therapeutic regimen against tuberculosis (TB) remains a long,... (Review)
Review
has recently surpassed HIV/AIDS as the leading cause of death by a single infectious agent. The standard therapeutic regimen against tuberculosis (TB) remains a long, expensive process involving a multidrug regimen, and the prominence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) strains continues to impede treatment success. An underexplored class of natural products-the capuramycin-type nucleoside antibiotics-have been shown to have potent anti-TB activity by inhibiting bacterial translocase I, a ubiquitous and essential enzyme that functions in peptidoglycan biosynthesis. The present review discusses current literature concerning the biosynthesis and chemical synthesis of capuramycin and analogs, seeking to highlight the potential of the capuramycin scaffold as a favorable anti-TB therapeutic that warrants further development.
Topics: Aminoglycosides; Antitubercular Agents; Bacteria; Biocatalysis; Biological Products; Drug Discovery; Humans; Metabolic Networks and Pathways; Multigene Family; Mycobacterium tuberculosis; Structure-Activity Relationship
PubMed: 30691073
DOI: 10.3390/molecules24030433