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Bioorganic & Medicinal Chemistry Mar 2023Among the various bacterial infections, tuberculosis continues to hold center stage. Its causative agent, Mycobacterium tuberculosis, possesses robust defense mechanisms... (Review)
Review
Among the various bacterial infections, tuberculosis continues to hold center stage. Its causative agent, Mycobacterium tuberculosis, possesses robust defense mechanisms against most front-line antibiotic drugs and host responses due to their complex cell membranes with unique lipid molecules. It is now well-established that bacteria change their membrane composition to optimize their environment to survive and elude drug action. Thus targeting membrane or membrane components is a promising avenue for exploiting the chemical space focussed on developing novel membrane-centric anti-bacterial small molecules. These approaches are more effective, non-toxic, and can attenuate resistance phenotype. We present the relevance of targeting the mycobacterial membrane as a practical therapeutic approach. The review highlights the direct and indirect targeting of membrane structure and function. Direct membrane targeting agents cause perturbation in the membrane potential and can cause leakage of the cytoplasmic contents. In contrast, indirect membrane targeting agents disrupt the function of membrane-associated proteins involved in cell wall biosynthesis or energy production. We discuss the chronological chemical improvements in various scaffolds targeting specific membrane-associated protein targets, their clinical evaluation, and up-to-date account of their ''mechanisms of action, potency, selectivity'' and limitations. The sources of anti-TB drugs/inhibitors discussed in this work have emerged from target-based identification, cell-based phenotypic screening, drug repurposing, and natural products. We believe this review will inspire the exploration of uncharted chemical space for informing the development of new scaffolds that can inhibit novel mycobacterial membrane targets.
Topics: Humans; Antitubercular Agents; Membrane Proteins; Mycobacterium tuberculosis; Tuberculosis; Bacterial Proteins
PubMed: 36804747
DOI: 10.1016/j.bmc.2023.117212 -
Drug Design, Development and Therapy 2021Tuberculosis (TB) is the most deadly infectious disease globally. Although most individuals achieve a cure, a substantial portion develop multi-drug resistant TB which... (Review)
Review
Tuberculosis (TB) is the most deadly infectious disease globally. Although most individuals achieve a cure, a substantial portion develop multi-drug resistant TB which is exceedingly difficult to treat, and the number of effective agents is dwindling. Development of new anti-tubercular medications is imperative to combat existing drug resistance and accelerate global eradication of TB. Pretomanid (PA-824) represents one of the newest drug classes (ie, nitroimidazooxazines) approved in 2019 by the United States Food and Drug Administration as part of a multi-drug regimen (with bedaquiline and linezolid, BPaL) and recommended by the World Health Organization (WHO) to treat extensively-resistant (XR-TB) and multi-drug resistant tuberculosis (MDR-TB). Approval was granted through the FDA's Limited Population Pathway for Antibacterial and Antifungal Drugs, which accelerates approval for antimicrobial drugs used to treat life-threatening or serious infections in a limited population with unmet need. This review details the pharmacology, efficacy, and safety of this new agent and describes evidence to date for its role in the treatment of drug resistant TB including published, ongoing, and planned studies.
Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Tuberculosis, Multidrug-Resistant
PubMed: 34234413
DOI: 10.2147/DDDT.S281639 -
Surgical Infections Mar 2022
Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Wrist
PubMed: 34612704
DOI: 10.1089/sur.2021.248 -
Future Medicinal Chemistry 2015Tuberculosis (TB) is a serious health problem causing 1.5 million deaths worldwide. After the discovery of first-line anti-TB drugs, the mortality rate declined sharply,... (Review)
Review
Tuberculosis (TB) is a serious health problem causing 1.5 million deaths worldwide. After the discovery of first-line anti-TB drugs, the mortality rate declined sharply, however, the emergence of drug-resistant strains and HIV co-infection have led to increased incidence of this disease. A number of new potential antitubercular drug candidates with novel modes of action have entered clinical trials in recent years. Compounds such as gatifloxacin, moxifloxacin and linezolid, the already known antibiotics are currently being evaluated for their anti-TB activity. OPC-67683 and TMC207 have been approved for the treatment of MDR-TB patients recently, while PA-824, SQ109, PNU-100480, AZD5847, LL3858, SQ609, SQ641, BTZ043, DC-159a, CPZEN-45, Q-203, DNB1, TBA-354 are in various phases of clinical and preclinical developments. This review evaluates the current status of TB drug development and future aspects.
Topics: Animals; Antitubercular Agents; Humans; Molecular Structure; Tuberculosis
PubMed: 26505682
DOI: 10.4155/fmc.15.128 -
Chemical Biology & Drug Design Nov 2015Mycobacterium tuberculosis is considered one of the most successful pathogens and multidrug-resistant tuberculosis, a disease that urgently requires new chemical... (Review)
Review
Mycobacterium tuberculosis is considered one of the most successful pathogens and multidrug-resistant tuberculosis, a disease that urgently requires new chemical entities to be developed for treatment. There are currently several new molecules under clinical investigation in the tuberculosis (TB) drug development pipeline. However, the complex lifestyle of M. tuberculosis within the host presents a barrier to the development of new drugs. In this review, we highlight the reasons that make TB drug discovery and development challenging as well as providing solutions, future directions and alternative approaches to new therapeutics for TB.
Topics: Animals; Antitubercular Agents; Drug Discovery; Humans; Mycobacterium tuberculosis; Treatment Outcome; Tuberculosis
PubMed: 25772393
DOI: 10.1111/cbdd.12549 -
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 -
Organic & Biomolecular Chemistry Jan 2016Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), an infection that has been declared a global public health emergency by the World Health... (Review)
Review
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), an infection that has been declared a global public health emergency by the World Health Organization. Current anti-TB therapies are limited in their efficacy and have failed to prevent the spread of TB, due to the long term drug compliance required and the genesis of multidrug-resistant strains (MDR). The number of chemotherapeutic agents currently available to treat MDR is limited, therefore there is a great need for new anti-TB drugs. Anti-TB peptides and peptidomimetics have emerged as an important and growing class of chemotherapeutic agents. This mini-review provides an update on peptides that exhibit very potent anti-TB activity, and their chemical syntheses, which could potentially be included in the pipeline for new anti-TB drug development.
Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Molecular Conformation; Mycobacterium tuberculosis; Peptides; Peptidomimetics; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 26645944
DOI: 10.1039/c5ob02298c -
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 -
Future Medicinal Chemistry Oct 2023Imidazo[2,1-]oxazole and 2,3-dihydroimidazo[2,1-]oxazole ring systems are commonly employed in therapeutically active molecules. In this article, the authors review the... (Review)
Review
Imidazo[2,1-]oxazole and 2,3-dihydroimidazo[2,1-]oxazole ring systems are commonly employed in therapeutically active molecules. In this article, the authors review the utilization of these core scaffolds as chemotherapeutic agents from 2018 to 2022. These scaffolds possess many important biological activities including antimicrobial and anticancer, among others. This review covers their biological activities and structure-activity relationships. One of the most important drugs in this class of compounds is the antitubercular agent delamanid. In this paper, the compounds structure-activity relationship and preclinical and clinical trial data are thoroughly presented.
Topics: Oxazoles; Antitubercular Agents; Structure-Activity Relationship
PubMed: 37814826
DOI: 10.4155/fmc-2023-0147 -
Tuberculosis (Edinburgh, Scotland) Mar 2019To complement the development of new or repurposed drugs for improving the treatment outcomes of drug-susceptible and drug-resistant tuberculosis, current insight also... (Review)
Review
To complement the development of new or repurposed drugs for improving the treatment outcomes of drug-susceptible and drug-resistant tuberculosis, current insight also focuses on the use of host-directed therapy. Metformin, a drug often used in the management of type 2 diabetes mellitus, has attracted attention by virtue of its favourable activity as an adjunctive agent against tuberculosis, discovered through laboratory and clinical studies. To definitively establish its role as a host-directed therapeutic in tuberculosis, more preclinical and clinical research is still required to better delineate its mechanism(s) of action and optimal clinical use.
Topics: Animals; Antitubercular Agents; Autophagy; Drug Interactions; Drug Therapy, Combination; Forecasting; Host-Pathogen Interactions; Humans; Immunity, Cellular; Latent Tuberculosis; Macrophages; Metformin; Mice; Mycobacterium tuberculosis; Oxidative Stress; Tuberculosis
PubMed: 30948180
DOI: 10.1016/j.tube.2019.02.004