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Journal of Clinical Pathology Mar 1967
Topics: Anti-Bacterial Agents; Antitubercular Agents; Drug Resistance, Microbial; Humans
PubMed: 5602517
DOI: 10.1136/jcp.20.2.219-a -
British Medical Journal Oct 1960
Topics: Antitubercular Agents; Ethionamide
PubMed: 13741471
DOI: 10.1136/bmj.2.5207.1207 -
Nature Communications Jun 2023Mycobacterium tuberculosis is one of the global leading causes of death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that...
Mycobacterium tuberculosis is one of the global leading causes of death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that have progressed through the drug discovery pipeline. These compounds are bicyclic nitroimidazoles that act as pro-drugs, requiring activation by a mycobacterial enzyme; however, the precise mechanisms of action of the active metabolite(s) are unclear. Here, we identify a molecular target of activated pretomanid and delamanid: the DprE2 subunit of decaprenylphosphoribose-2'-epimerase, an enzyme required for the synthesis of cell wall arabinogalactan. We also provide evidence for an NAD-adduct as the active metabolite of pretomanid. Our results highlight DprE2 as a potential antimycobacterial target and provide a foundation for future exploration into the active metabolites and clinical development of pretomanid and delamanid.
Topics: Antitubercular Agents; Molecular Targeted Therapy; Mycobacterium tuberculosis; Alcohol Oxidoreductases; Nitroimidazoles; Cell Wall; Drug Resistance; Prodrugs; Spectrophotometry; NAD; Kinetics
PubMed: 37380634
DOI: 10.1038/s41467-023-39300-z -
Microbiology Spectrum Jan 2017While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for... (Review)
Review
While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in clinical settings. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of posttreatment relapse. Some promising drugs to treat tuberculosis, such as rifampin and bedaquiline, only kill nonreplicating M. tuberculosisin vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high-throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores.
Topics: Antitubercular Agents; Drug Evaluation, Preclinical; Drug Tolerance; High-Throughput Screening Assays; Microbial Viability; Mycobacterium tuberculosis
PubMed: 28233509
DOI: 10.1128/microbiolspec.TBTB2-0031-2016 -
Trends in Immunology Sep 2023Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global... (Review)
Review
Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global dissemination of drug resistance across Mycobacterium tuberculosis (Mtb) strains, causative of TB, resulted in an estimated 450 000 cases of drug-resistant (DR) TB in 2021. Dysregulated immune responses have been observed in patients with multidrug resistant (MDR) TB, but the effects of drug resistance acquisition and impact on host immunity remain obscure. In this review, we compile studies that span aspects of altered host-pathogen interactions and highlight research that explores how drug resistance and immunity might intersect. Understanding the immune processes differentially induced during DR TB would aid the development of rational therapeutics and vaccines for patients with MDR TB.
Topics: Humans; Rifampin; Antitubercular Agents; Tuberculosis; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 37543504
DOI: 10.1016/j.it.2023.07.003 -
Clinics in Chest Medicine Dec 2019Tuberculosis (TB) has now surpassed HIV as the leading infectious cause of death, and treatment success rates are declining. Multidrug-resistant TB, extensively... (Review)
Review
Tuberculosis (TB) has now surpassed HIV as the leading infectious cause of death, and treatment success rates are declining. Multidrug-resistant TB, extensively drug-resistant TB, and even totally drug-resistant TB threaten to further destabilize disease control efforts. The second wave in TB drug development, which includes the diarylquinoline, bedaquiline, and the nitroimidazoles delamanid and pretomanid, may offer options for simpler, shorter, and potentially all-oral regimens to treat drug-resistant TB. The "third wave" of TB drug development includes numerous promising compounds, including less toxic versions of older drug classes and candidates with novel mechanisms of action.
Topics: Antitubercular Agents; Diarylquinolines; Humans; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 31731986
DOI: 10.1016/j.ccm.2019.08.001 -
PLoS Pathogens Sep 2019Stewart Cole and colleagues determined the complete genome sequence of Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), in 1998 [1]. This...
Stewart Cole and colleagues determined the complete genome sequence of Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), in 1998 [1]. This was a landmark achievement that heralded a new age in TB drug discovery. With the genome sequence in hand, drug discoverers suddenly had thousands of new potential targets to explore. But the excitement has since faded [2]. It is unquestioned that genomics has transformed our understanding of the biology of this pathogen. However, the expectation that the Mtb genome sequence would rapidly lead to new therapeutic interventions remains unfulfilled [3]. One of the (many) reasons for this unrealized potential is that our tools to systematically interrogate the Mtb genome and its drug targets-so-called functional genomics-have been limited. In this Pearl, I argue that the recent development of robust CRISPR-based genetics in Mtb [4] overcomes many prior limitations and holds the potential to close the gap between genomics and TB drug discovery.
Topics: Antitubercular Agents; Bacterial Proteins; CRISPR-Cas Systems; Drug Delivery Systems; Drug Discovery; Genomics; Mycobacterium tuberculosis; Tuberculosis
PubMed: 31536613
DOI: 10.1371/journal.ppat.1007975 -
Molecular Microbiology Dec 2006For decades after its introduction, the mechanisms of action of the front-line antituberculosis therapeutic agent isoniazid (INH) remained unclear. Recent developments... (Review)
Review
For decades after its introduction, the mechanisms of action of the front-line antituberculosis therapeutic agent isoniazid (INH) remained unclear. Recent developments have shown that peroxidative activation of isoniazid by the mycobacterial enzyme KatG generates reactive species that form adducts with NAD(+) and NADP(+) that are potent inhibitors of lipid and nucleic acid biosynthetic enzymes. A direct role for some isoniazid-derived reactive species, such as nitric oxide, in inhibiting mycobacterial metabolic enzymes has also been shown. The concerted effects of these activities - inhibition of cell wall lipid synthesis, depletion of nucleic acid pools and metabolic depression - drive the exquisite potency and selectivity of this agent. To understand INH action and resistance fully, a synthesis of knowledge is required from multiple separate lines of research - including molecular genetic approaches, in vitro biochemical studies and free radical chemistry - which is the intent of this review.
Topics: Antitubercular Agents; Isoniazid; Mycobacterium tuberculosis; NAD
PubMed: 17074073
DOI: 10.1111/j.1365-2958.2006.05467.x -
Biomedicine & Pharmacotherapy =... Feb 2024Given that the disease progression of tuberculosis (TB) is primarily related to the host's immune status, it has been gradually realized that chemotherapy that targets... (Review)
Review
Given that the disease progression of tuberculosis (TB) is primarily related to the host's immune status, it has been gradually realized that chemotherapy that targets the bacteria may never, on its own, wholly eradicate Mycobacterium tuberculosis, the causative agent of TB. The concept of host-directed therapy (HDT) with immune adjuvants has emerged. HDT could potentially interfere with infection and colonization by the pathogens, enhance the protective immune responses of hosts, suppress the overwhelming inflammatory responses, and help to attain a state of homeostasis that favors treatment efficacy. However, the HDT drugs currently being assessed in combination with anti-TB chemotherapy still face the dilemmas arising from side effects and high costs. Natural products are well suited to compensate for these shortcomings by having gentle modulatory effects on the host immune responses with less immunopathological damage at a lower cost. In this review, we first summarize the profiles of anti-TB immunology and the characteristics of HDT. Then, we focus on the rationale and challenges of developing and implementing natural products-based HDT. A succinct report of the medications currently being evaluated in clinical trials and preclinical studies is provided. This review aims to promote target-based screening and accelerate novel TB drug discovery.
Topics: Humans; Antitubercular Agents; Tuberculosis; Mycobacterium tuberculosis; Adjuvants, Immunologic; Immunity
PubMed: 38171242
DOI: 10.1016/j.biopha.2023.116087 -
Trends in Microbiology Mar 2024The aetiologic agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), can survive, persist, and proliferate in a variety of heterogeneous subcellular... (Review)
Review
The aetiologic agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), can survive, persist, and proliferate in a variety of heterogeneous subcellular compartments. Therefore, TB chemotherapy requires antibiotics crossing multiple biological membranes to reach distinct subcellular compartments and target these bacterial populations. These compartments are also dynamic, and our understanding of intracellular pharmacokinetics (PK) often represents a challenge for antitubercular drug development. In recent years, the development of high-resolution imaging approaches in the context of host-pathogen interactions has revealed the intracellular distribution of antibiotics at a new level, yielding discoveries with important clinical implications. In this review, we describe the current knowledge regarding cellular PK of antibiotics and the complexity of drug distribution within the context of TB. We also discuss the recent advances in quantitative imaging and highlight their applications for drug development in the context of how intracellular environments and microbial localisation affect TB treatment efficacy.
Topics: Humans; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis; Host-Pathogen Interactions; Treatment Outcome
PubMed: 37709598
DOI: 10.1016/j.tim.2023.08.009