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Microbiology (Reading, England) May 2019Bacterial persisters are a subpopulation of cells that exhibit phenotypic resistance during exposure to a lethal dose of antibiotics. They are difficult to target and... (Review)
Review
Bacterial persisters are a subpopulation of cells that exhibit phenotypic resistance during exposure to a lethal dose of antibiotics. They are difficult to target and thought to contribute to the long treatment duration required for tuberculosis. Understanding the molecular and cellular biology of persisters is critical to finding new tuberculosis drugs that shorten treatment. This review focuses on mycobacterial persisters and describes the challenges they pose in tuberculosis therapy, their characteristics and formation, how persistence leads to resistance, and the current approaches being used to target persisters within mycobacterial drug discovery.
Topics: Animals; Antitubercular Agents; Drug Discovery; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 30775961
DOI: 10.1099/mic.0.000760 -
Journal of Genetics and Genomics = Yi... Jan 2017Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the... (Review)
Review
Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance.
Topics: Animals; Antitubercular Agents; Drug Resistance, Bacterial; Genomics; Humans; Molecular Targeted Therapy; Mycobacterium tuberculosis; Tuberculosis
PubMed: 28117224
DOI: 10.1016/j.jgg.2016.10.002 -
Gene Feb 2018Lipid metabolism forms the heart and soul of Mycobacterium tuberculosis life cycle. Starting from macrophage invasion at cholesterol rich micro-domains to a sustainable...
Lipid metabolism forms the heart and soul of Mycobacterium tuberculosis life cycle. Starting from macrophage invasion at cholesterol rich micro-domains to a sustainable survival for infection by utilizing cholesterol, Mycobacterium displays the nexus of metabolic pathways around host derived lipids. mce4 operon acts as cholesterol import system in M. tuberculosis and here we demonstrate role of mce4A gene of this operon in cholesterol catabolism. Here M. tuberculosis H37Rv overexpressing Rv3499c (mce4A) recombinant was used as a model to decipher the metabolic flux during intake and utilization of host lipids by mycobacteria. We analysed the impact of mce4A expression on carbon shift initiated during cholesterol utilization necessary for long term survival of mycobacterium. Through transcriptional analysis, upregulation in methylcitrate cycle (MCC) and methylmalonyl pathway (MMP) genes was observed in Rv3499c overexpressing recombinants of M. tuberculosis H37Rv. Up-regulation of methylmalonyl pathway associated enzyme encoding genes increased accumulation of virulence associated mycobacterial lipids phthiocerol dimycocerates (PDIM) and sulfolipid (SL1). We demonstrate that MCC and MMP associated enzyme encoding genes are upregulated upon mce4A overexpression and lead to enhanced accumulation of PDIM and SL1 which are responsible for pathogenicity of M. tuberculosis.
Topics: Bacterial Proteins; Cholesterol; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Gene Regulatory Networks; Lipids; Mycobacterium tuberculosis; Protein Interaction Maps; Recombinant Proteins; Up-Regulation; Virulence
PubMed: 28988960
DOI: 10.1016/j.gene.2017.09.062 -
Microbiology Spectrum Jun 2017Coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food... (Review)
Review
Coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food during infection. Simply put, bacterial pathogens are just looking for food. As a consequence, the host has developed strategies to limit nutrients for the bacterium by containment of the intruder in a pathogen-containing vacuole and/or by actively depleting nutrients from the intracellular space, a process called nutritional immunity. Since metabolism is a prerequisite for virulence, such pathways could potentially be good targets for antimicrobial therapies. In this chapter, we review the current knowledge about the diet of , with a focus on amino acid and cofactors, discuss evidence for the bacilli's nutritionally independent lifestyle in the host, and evaluate strategies for new chemotherapeutic interventions.
Topics: Amino Acids; Antitubercular Agents; Coenzymes; Host-Pathogen Interactions; Intracellular Space; Macrophages; Metabolomics; Mycobacterium tuberculosis; Nutritional Physiological Phenomena; Purines; Tuberculosis; Vacuoles; Virulence
PubMed: 28597811
DOI: 10.1128/microbiolspec.TBTB2-0030-2016 -
Emerging Infectious Diseases Mar 2019Mycobacterium tuberculosis RD-Rio strains are still rare in the former Soviet Union countries and Asia. We describe a strain in Kazakhstan that belongs to the RD-Rio...
Mycobacterium tuberculosis RD-Rio strains are still rare in the former Soviet Union countries and Asia. We describe a strain in Kazakhstan that belongs to the RD-Rio secondary branch, which is endemic to northwest Russia and eastern Europe. Although RD-Rio strains are frequently multidrug resistant, this heterogeneous branch included only drug-susceptible isolates.
Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Kazakhstan; Microbial Sensitivity Tests; Minisatellite Repeats; Mycobacterium tuberculosis; Phylogeny; Population Surveillance; Tuberculosis
PubMed: 30789328
DOI: 10.3201/eid2503.181179 -
Current Opinion in Microbiology Oct 2018Claiming close to two million lives each year, tuberculosis is now the leading cause of death from an infectious disease. The rise in number of Mycobacterium... (Review)
Review
Claiming close to two million lives each year, tuberculosis is now the leading cause of death from an infectious disease. The rise in number of Mycobacterium tuberculosis (Mtb) strains resistant to existing TB drugs has underscored the urgent need to develop new antimycobacterials with novel mechanisms of action. To meet this need, a drug pipeline has been established that is populated with new and repurposed drugs. Recent advances in identifying molecules with inhibitory activity against Mtb under conditions modelled on those encountered during infection, and in elucidating their mechanisms of action, have primed the pipeline with promising drug/target couples, hit compounds and new targets. In this review, we highlight recent advances and emerging areas of opportunity in this field.
Topics: Animals; Antitubercular Agents; Drug Design; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 29482115
DOI: 10.1016/j.mib.2018.02.006 -
Infectious Disease Clinics of North... Dec 2020Multidrug-resistant Mycobacterium tuberculosis remains a major public health threat; its management poses a significant economic burden. Treatment requires a... (Review)
Review
Multidrug-resistant Mycobacterium tuberculosis remains a major public health threat; its management poses a significant economic burden. Treatment requires a programmatic approach with access to laboratory services, second-line medications, and adequate clinical resources. In recent years, we have seen rapid developments in diagnostic techniques with whole genome sequencing-based drug susceptibility prediction now in reach, an array of new drugs that transform treatment regimens to purely oral formulations, and a steady stream of multinational trials that inform us about most efficient combinations. Our hope is that the current momentum keeps the ambitious goal to end tuberculosis in 2030 in reach.
Topics: Anti-Bacterial Agents; Antitubercular Agents; Early Diagnosis; Genome, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing
PubMed: 33011048
DOI: 10.1016/j.idc.2020.06.001 -
Journal of the South African Veterinary... Apr 2016Members of the Mycobacterium tuberculosis complex (MTC) cause tuberculosis (TB) in both animals and humans. In this article, three animal-adapted MTC strains that are... (Review)
Review
Members of the Mycobacterium tuberculosis complex (MTC) cause tuberculosis (TB) in both animals and humans. In this article, three animal-adapted MTC strains that are endemic to the southern African subregion - that is, Mycobacterium suricattae, Mycobacterium mungi, and the dassie bacillus - are reviewed with a focus on clinical and pathological presentations, geographic distribution, genotyping methods, diagnostic tools and evolution. Moreover, factors influencing the transmission and establishment of TB pathogens in novel host populations, including ecological, immunological and genetic factors of both the host and pathogen, are discussed. The risks associated with these infections are currently unknown and further studies will be required for greater understanding of this disease in the context of the southern African ecosystem.
Topics: Africa, Southern; Animals; Biological Evolution; Genotyping Techniques; Herpestidae; Hyraxes; Mycobacterium tuberculosis; Phylogeny; Tuberculosis
PubMed: 27246904
DOI: 10.4102/jsava.v87i1.1322 -
Yi Chuan = Hereditas Oct 2016The occurance and prevalence of multidrug-resistant tuberculosis poses a serious threat to the global tuberculosis control. Ethambutol (EMB) is one of the first-line... (Review)
Review
The occurance and prevalence of multidrug-resistant tuberculosis poses a serious threat to the global tuberculosis control. Ethambutol (EMB) is one of the first-line anti-tuberculosis drugs, which is usually used in combination with isoniazid and rifampicin for treating pan-sensitive tuberculosis, and it can also be used in drug-resistant tuberculosis. However, the situation of EMB resistance is alarmingly high, especially in multi-drug resistant tuberculosis. In China, EMB resistance rate in the previously treated cases was up to 17.2% and showed an increased tendency. What was worse, 51.3%-66.7% of multidrug-resistant tuberculosis cases were resistant to EMB. Thus, it is important to understand the drug resistance mechanism of EMB, which will help to slow down the drug resistance rate of EMB. In this review, we focus on the current status of EMB resistance, the effects of EMB and the mechanisms of EMB resistance in Mycobacterium tuberculosis.
Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Bacterial; Ethambutol; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 27806932
DOI: 10.16288/j.yczz.16-111 -
Proceedings of the National Academy of... Apr 2022Current chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been...
Current chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug–drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, host environments profoundly affect the bacterial metabolic state and drug efficacy, limiting the accuracy of predictions based on in vitro assays alone. In this study, we utilized conditional Mtb knockdown mutants of essential genes as an experimentally tractable surrogate for drug treatment and probe the relationship between Mtb carbon metabolism and chemical–genetic interactions (CGIs). We examined the antitubercular drugs isoniazid, rifampicin, and moxifloxacin and found that CGIs are differentially responsive to the metabolic state, defining both environment-independent and -dependent interactions. Specifically, growth on the in vivo–relevant carbon source, cholesterol, reduced rifampicin efficacy by altering mycobacterial cell surface lipid composition. We report that a variety of perturbations in cell wall synthesis pathways restore rifampicin efficacy during growth on cholesterol, and that both environment-independent and cholesterol-dependent in vitro CGIs could be leveraged to enhance bacterial clearance in the mouse infection model. Our findings present an atlas of chemical–genetic–environmental interactions that can be used to optimize drug–drug interactions, as well as provide a framework for understanding in vitro correlates of in vivo efficacy.
Topics: Antitubercular Agents; Carbon; Cell Wall; Drug Interactions; Gene-Environment Interaction; Humans; Mycobacterium tuberculosis
PubMed: 35380903
DOI: 10.1073/pnas.2201632119