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Trends in Microbiology Jun 2018In this infographic, the genetics, phylogeny, physiology, and pathogenesis mechanisms of Mycobacterium tuberculosis are shown. Mycobacterium tuberculosis is the...
In this infographic, the genetics, phylogeny, physiology, and pathogenesis mechanisms of Mycobacterium tuberculosis are shown. Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), the leading cause of death due to a single infectious agent, claiming 1.7 million lives in 2016. Of the deaths attributable to TB in 2016, 22% occurred in people coinfected with HIV, and close to 5% of the 10.4 million incident cases of this disease were resistant to at least two of the first-line TB drugs. In this infographic, we describe the fundamental features of the genetics, phylogeny, and physiology of this member of the phylum Actinobacteria, which is associated increasingly with drug resistance mediated by mutations and rearrangements in its single, circular chromosome. We also highlight the key pathogenesis mechanisms employed by this slow-growing, facultative intracellular bacterium, which include avoidance of host cell clearance by arrest of the normal macrophage maturation process.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Macrophages; Mycobacterium tuberculosis; Phylogeny; Tuberculosis
PubMed: 29580884
DOI: 10.1016/j.tim.2018.02.012 -
Microbiology Spectrum Jul 2019is the cause of tuberculosis (TB), a disease which continues to overwhelm health systems in endemic regions despite the existence of effective combination chemotherapy... (Review)
Review
is the cause of tuberculosis (TB), a disease which continues to overwhelm health systems in endemic regions despite the existence of effective combination chemotherapy and the widespread use of a neonatal anti-TB vaccine. For a professional pathogen, retains a surprisingly large proportion of the metabolic repertoire found in nonpathogenic mycobacteria with very different lifestyles. Moreover, evidence that additional functions were acquired during the early evolution of the complex suggests the organism has adapted (and augmented) the metabolic pathways of its environmental ancestor to persistence and propagation within its obligate human host. A better understanding of pathogenicity, however, requires the elucidation of metabolic functions under disease-relevant conditions, a challenge complicated by limited knowledge of the microenvironments occupied and nutrients accessed by bacilli during host infection, as well as the reliance in experimental mycobacteriology on a restricted number of experimental models with variable relevance to clinical disease. Here, we consider metabolism within the framework of an intimate host-pathogen coevolution. Focusing on recent advances in our understanding of mycobacterial metabolic function, we highlight unusual adaptations or departures from the better-characterized model intracellular pathogens. We also discuss the impact of these mycobacterial "innovations" on the susceptibility of to existing and experimental anti-TB drugs, as well as strategies for targeting metabolic pathways. Finally, we offer some perspectives on the key gaps in the current knowledge of fundamental mycobacterial metabolism and the lessons which might be learned from other systems.
Topics: Animals; Antitubercular Agents; Humans; Metabolic Networks and Pathways; Mycobacterium tuberculosis; Tuberculosis; Virulence
PubMed: 31350832
DOI: 10.1128/microbiolspec.GPP3-0067-2019 -
Nature Reviews. Microbiology Aug 2018Metabolism was once relegated to the supply of energy and biosynthetic precursors, but it has now become clear that it is a specific mediator of nearly all physiological... (Review)
Review
Metabolism was once relegated to the supply of energy and biosynthetic precursors, but it has now become clear that it is a specific mediator of nearly all physiological processes. In the context of microbial pathogenesis, metabolism has expanded outside its canonical role in bacterial replication. Among human pathogens, this expansion has emerged perhaps nowhere more visibly than for Mycobacterium tuberculosis, the causative agent of tuberculosis. Unlike most pathogens, M. tuberculosis has evolved within humans, which are both host and reservoir. This makes unrestrained replication and perpetual quiescence equally incompatible strategies for survival as a species. In this Review, we summarize recent work that illustrates the diversity of metabolic functions that not only enable M. tuberculosis to establish and maintain a state of chronic infection within the host but also facilitate its survival in the face of drug pressure and, ultimately, completion of its life cycle.
Topics: Energy Metabolism; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Tuberculosis; Virulence
PubMed: 29691481
DOI: 10.1038/s41579-018-0013-4 -
Trends in Microbiology Oct 2020Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18%... (Review)
Review
Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18% of recurrent cases of TB are multidrug-resistant (MDR) or rifampicin-resistant. Recent evidence has shown that certain drug-resistant strains of Mtb modulate host metabolic reprogramming, and therefore immune responses, during infection. However, it remains unclear how widespread these mechanisms are among circulating MDR Mtb strains and what impact drug-resistance-conferring mutations have on immunometabolism during TB. While few studies have directly addressed metabolic reprogramming in the context of drug-resistant Mtb infection, previous literature examining how drug-resistance mutations alter Mtb physiology and differences in the immune response to drug-resistant Mtb provides significant insights into how drug-resistant strains of Mtb differentially impact immunometabolism.
Topics: Animals; Antitubercular Agents; Bacterial Proteins; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis
PubMed: 32409147
DOI: 10.1016/j.tim.2020.04.010 -
Journal of Medical Microbiology Nov 2015Some species of the Mycobacterium tuberculosis complex (MTBC), particularly Mycobacterium tuberculosis, which causes human tuberculosis (TB), are the first cause of... (Review)
Review
Some species of the Mycobacterium tuberculosis complex (MTBC), particularly Mycobacterium tuberculosis, which causes human tuberculosis (TB), are the first cause of death linked to a single pathogen worldwide. In the last decades, evolutionary studies have much improved our knowledge on MTBC history and have highlighted its long co-evolution with humans. Its ability to remain latent in humans, the extraordinary proportion of asymptomatic carriers (one-third of the entire human population), the deadly epidemics and the observed increasing level of resistance to antibiotics are proof of its evolutionary success. Many MTBC molecular signatures show not only that these bacteria are a model of adaptation to humans but also that they have influenced human evolution. Owing to the unbalance between the number of asymptomatic carriers and the number of patients with active TB, some authors suggest that infection by MTBC could have a protective role against active TB disease and also against other pathologies. However, it would be inappropriate to consider these infectious pathogens as commensals or symbionts, given the level of morbidity and mortality caused by TB.
Topics: Animals; Biological Evolution; Humans; Mycobacterium tuberculosis; Phylogeny; Tuberculosis
PubMed: 26385049
DOI: 10.1099/jmm.0.000171 -
Microbiology Spectrum Mar 2019has evolved to become the single greatest cause of death from an infectious agent. The pathogen spends most of its infection cycle in its human host within a phagocyte.... (Review)
Review
has evolved to become the single greatest cause of death from an infectious agent. The pathogen spends most of its infection cycle in its human host within a phagocyte. The bacterium has evolved to block the normal maturation and acidification of its phagosome and resides in a vacuole contiguous with the early endosomal network. Cytokine-mediated activation of the host cell can overcome this blockage, and an array of antimicrobial responses can limit its survival. The survival of in its host cell is fueled predominantly by fatty acids and cholesterol. The ability of to degrade sterols is an unusual metabolic characteristic that was likely retained from a saprophytic ancestor. Recent results with fluorescent reporter strains demonstrate that bacterial survival differs with the host macrophage population. Tissue-resident alveolar macrophages, which are biased towards an alternatively activated, M2-like phenotype, are more permissive to bacterial growth than monocyte-derived, inflammatory, M1-like interstitial macrophages. The differential growth of the bacterium in these different phagocyte populations appears to be linked to host cell metabolism.
Topics: Animals; Anti-Bacterial Agents; Cytokines; Host-Pathogen Interactions; Humans; Macrophages; Microbial Viability; Mycobacterium tuberculosis; Phagocytes; Phagosomes; Tuberculosis; Vacuoles
PubMed: 30848232
DOI: 10.1128/microbiolspec.BAI-0001-2019 -
International Journal of... 2018Mycobacterium tuberculosis (Mtb) strains H37Ra and H37Rv are commonly used to study new and re-evaluate old antituberculous agents with respect to their pharmacodynamic...
BACKGROUND
Mycobacterium tuberculosis (Mtb) strains H37Ra and H37Rv are commonly used to study new and re-evaluate old antituberculous agents with respect to their pharmacodynamic effects in vitro. The differences in membrane proteins and, in particular, differences in carrier proteins between Mtb H37Ra and Mtb H37Rv may have an impact on antibiotic potency. The question of whether H37Ra can be used as a reliable surrogate for H37Rv and clinical strains has not been addressed sufficiently. The purpose of this study is to provide a full comparison of susceptibility data of the most common antituberculosis (TB) agents against both Mtb strains.
METHODS
In addition to a literature review, in vitro checkerboard susceptibility study was conducted comparing the in vitro minimum inhibitory concentration (MIC) of 16 common antituberculous drugs against H37Ra and H37Rv. Heifets-Sanchez TB agar drug susceptibility plates were utilized.
RESULTS
Half of the antibiotics demonstrated similar growth inhibition against both strains, while slightly differing MIC values were found for 7 of 16 drugs. With the exception of rifampicin, no marked difference in MIC against H37Ra and H37Rv was observed.
CONCLUSION
While neither the attenuated (H37Ra) nor the virulent strain (H37Rv) is a clinical strain, both strains predicted MICs of clinical isolates equally well, when comparing the current in vitro results to clinical susceptibility data in the literature. H37Ra comes with the benefits of lower experimental costs and less administrative barriers including the requirement of a biosafety Level III environment.
Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis
PubMed: 29900893
DOI: 10.4103/ijmy.ijmy_33_18 -
Journal of Infection and Public Health 2018Rifampicin (RIF) plays a pivotal role in the treatment of tuberculosis due to its bactericidal effects. Because the action of RIF is on rpoB gene encoding RNA polymerase... (Review)
Review
BACKGROUND
Rifampicin (RIF) plays a pivotal role in the treatment of tuberculosis due to its bactericidal effects. Because the action of RIF is on rpoB gene encoding RNA polymerase β subunit, 95% of RIF resistant mutations are present in rpoB gene. The majority of the mutations in rpoB gene are found within an 81bp RIF-resistance determining region (RRDR).
METHODOLOGY
Literatures on RIF resistant mutations published between 2010 and 2016 were thoroughly reviewed.
RESULTS
The most commonly mutated codons in RRDR of rpoB gene are 531, 526 and 516. The possibilities of absence of mutation in RRDR of rpoB gene in MDR-TB isolates in few studies was due to existence of other rare rpoB mutations outside RRDR or different mechanism of rifampicin resistance.
CONCLUSION
Molecular methods which can identify extensive mutations associated with multiple anti-tuberculous drugs are in urgent need so that the research on drug resistant mutations should be extended.
Topics: Antibiotics, Antitubercular; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Mutation, Missense; Mycobacterium tuberculosis; Rifampin; Tuberculosis
PubMed: 29706316
DOI: 10.1016/j.jiph.2018.04.005 -
The Journal of Infectious Diseases Nov 2017Measuring tuberculosis transmission is exceedingly difficult, given the remarkable variability in the timing of clinical disease after Mycobacterium tuberculosis... (Review)
Review
Measuring tuberculosis transmission is exceedingly difficult, given the remarkable variability in the timing of clinical disease after Mycobacterium tuberculosis infection; incident disease can result from either a recent (ie, weeks to months) or a remote (ie, several years to decades) infection event. Although we cannot identify with certainty the timing and location of tuberculosis transmission for individuals, approaches for estimating the individual probability of recent transmission and for estimating the fraction of tuberculosis cases due to recent transmission in populations have been developed. Data used to estimate the probable burden of recent transmission include tuberculosis case notifications in young children and trends in tuberculin skin test and interferon γ-release assays. More recently, M. tuberculosis whole-genome sequencing has been used to estimate population levels of recent transmission, identify the distribution of specific strains within communities, and decipher chains of transmission among culture-positive tuberculosis cases. The factors that drive the transmission of tuberculosis in communities depend on the burden of prevalent tuberculosis; the ways in which individuals live, work, and interact (eg, congregate settings); and the capacity of healthcare and public health systems to identify and effectively treat individuals with infectious forms of tuberculosis. Here we provide an overview of these factors, describe tools for measurement of ongoing transmission, and highlight knowledge gaps that must be addressed.
Topics: Disease Transmission, Infectious; Environmental Exposure; Humans; Molecular Epidemiology; Mycobacterium tuberculosis; Risk Factors; Tuberculosis
PubMed: 29112745
DOI: 10.1093/infdis/jix354 -
Microbiology (Reading, England) May 2024(Mtb) senses and adapts to host environmental cues as part of its pathogenesis. One important cue sensed by Mtb is the acidic pH of its host niche - the macrophage.... (Review)
Review
(Mtb) senses and adapts to host environmental cues as part of its pathogenesis. One important cue sensed by Mtb is the acidic pH of its host niche - the macrophage. Acidic pH induces widespread transcriptional and metabolic remodelling in Mtb. These adaptations to acidic pH can lead Mtb to slow its growth and promote pathogenesis and antibiotic tolerance. Mutants defective in pH-dependent adaptations exhibit reduced virulence in macrophages and animal infection models, suggesting that chemically targeting these pH-dependent pathways may have therapeutic potential. In this review, we discuss mechanisms by which Mtb regulates its growth and metabolism at acidic pH. Additionally, we consider the therapeutic potential of disrupting pH-driven adaptations in Mtb and review the growing class of compounds that exhibit pH-dependent activity or target pathways important for adaptation to acidic pH.
Topics: Mycobacterium tuberculosis; Hydrogen-Ion Concentration; Adaptation, Physiological; Animals; Humans; Tuberculosis; Macrophages; Virulence; Gene Expression Regulation, Bacterial; Bacterial Proteins; Antitubercular Agents
PubMed: 38717801
DOI: 10.1099/mic.0.001458