-
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 -
The Journal of Antimicrobial... May 2018Drug-resistant TB (DR-TB) remains a significant challenge in TB treatment and control programmes worldwide. Advances in sequencing technology have significantly... (Review)
Review
Drug-resistant TB (DR-TB) remains a significant challenge in TB treatment and control programmes worldwide. Advances in sequencing technology have significantly increased our understanding of the mechanisms of resistance to anti-TB drugs. This review provides an update on advances in our understanding of drug resistance mechanisms to new, existing drugs and repurposed agents. Recent advances in WGS technology hold promise as a tool for rapid diagnosis and clinical management of TB. Although the standard approach to WGS of Mycobacterium tuberculosis is slow due to the requirement for organism culture, recent attempts to sequence directly from clinical specimens have improved the potential to diagnose and detect resistance within days. The introduction of new databases may be helpful, such as the Relational Sequencing TB Data Platform, which contains a collection of whole-genome sequences highlighting key drug resistance mutations and clinical outcomes. Taken together, these advances will help devise better molecular diagnostics for more effective DR-TB management enabling personalized treatment, and will facilitate the development of new drugs aimed at improving outcomes of patients with this disease.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Genes, Bacterial; Genotyping Techniques; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Time; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing
PubMed: 29360989
DOI: 10.1093/jac/dkx506 -
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 -
Microbiology Spectrum Nov 2016The interaction between the host and the pathogen is extremely complex and is affected by anatomical, physiological, and immunological diversity in the... (Review)
Review
The interaction between the host and the pathogen is extremely complex and is affected by anatomical, physiological, and immunological diversity in the microenvironments, leading to phenotypic diversity of the pathogen. Phenotypic heterogeneity, defined as nongenetic variation observed in individual members of a clonal population, can have beneficial consequences especially in fluctuating stressful environmental conditions. This is all the more relevant in infections caused by Mycobacterium tuberculosis wherein the pathogen is able to survive and often establish a lifelong persistent infection in the host. Recent studies in tuberculosis patients and in animal models have documented the heterogeneous and diverging trajectories of individual lesions within a single host. Since the fate of the individual lesions appears to be determined by the local tissue environment rather than systemic response of the host, studying this heterogeneity is very relevant to ensure better control and complete eradication of the pathogen from individual lesions. The heterogeneous microenvironments greatly enhance M. tuberculosis heterogeneity influencing the growth rates, metabolic potential, stress responses, drug susceptibility, and eventual lesion resolution. Single-cell approaches such as time-lapse microscopy using microfluidic devices allow us to address cell-to-cell variations that are often lost in population-average measurements. In this review, we focus on some of the factors that could be considered as drivers of phenotypic heterogeneity in M. tuberculosis as well as highlight some of the techniques that are useful in addressing this issue.
Topics: Animals; Antitubercular Agents; Disease Models, Animal; Genetic Heterogeneity; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Phenotype; Tuberculosis
PubMed: 27837741
DOI: 10.1128/microbiolspec.TBTB2-0021-2016 -
Microbiology Spectrum Jun 2014Lipidomics is a distinct subspecialty of metabolomics concerned with hydrophobic molecules that organize into membranes. Most of the lipid classes present in... (Review)
Review
Lipidomics is a distinct subspecialty of metabolomics concerned with hydrophobic molecules that organize into membranes. Most of the lipid classes present in Mycobacterium tuberculosis are found only in Actinobacteria and show extreme structural diversity. This article highlights the conceptual basis and the practical challenges associated with the mass spectrometry-based lipidomic study of M. tuberculosis to solve basic questions about the virulence of this lipid-laden organism.
Topics: Lipid Metabolism; Lipids; Mass Spectrometry; Metabolomics; Mycobacterium tuberculosis
PubMed: 26103971
DOI: 10.1128/microbiolspec.MGM2-0033-2013 -
Genes Jan 2019There are an estimated 10 million new cases of tuberculosis worldwide annually, with 282,000 new or relapsed cases each year reported from the Americas. With... (Review)
Review
There are an estimated 10 million new cases of tuberculosis worldwide annually, with 282,000 new or relapsed cases each year reported from the Americas. With improvements in genome sequencing technology, it is now possible to study the genetic diversity of tuberculosis with much greater resolution. Although tuberculosis bacteria do not engage in horizontal gene transfer, the genome is far more variable than previously thought. The study of genome-wide variation in tuberculosis has improved our understanding of the evolutionary origins of tuberculosis, the arrival of tuberculosis in Latin America, the genetic determinants of drug resistance, and lineage-specific associations with important clinical phenotypes. This article reviews what is known about the arrival of tuberculosis in Latin America, the genetic diversity of tuberculosis in Latin America, and the genotypic determinants of clinical phenotypes.
Topics: Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; South America; Tuberculosis
PubMed: 30654542
DOI: 10.3390/genes10010053 -
Microbiology Spectrum Mar 2017Reversible protein phosphorylation is the most common type of epigenetic posttranslational modification in living cells used as a major regulation mechanism of... (Review)
Review
Reversible protein phosphorylation is the most common type of epigenetic posttranslational modification in living cells used as a major regulation mechanism of biological processes. The Mycobacterium tuberculosis genome encodes for 11 serine/threonine protein kinases that are responsible for sensing environmental signals to coordinate a cellular response to ensure the pathogen's infectivity, survival, and growth. To overcome killing mechanisms generated within the host during infection, M. tuberculosis enters a state of nonreplicating persistence that is characterized by arrested growth, limited metabolic activity, and phenotypic resistance to antimycobacterial drugs. In this article we focus our attention on the role of M. tuberculosis serine/threonine protein kinases in sensing the host environment to coordinate the bacilli's physiology, including growth, cell wall components, and central metabolism, to establish a persistent infection.
Topics: Animals; Epigenesis, Genetic; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Phosphorylation; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases
PubMed: 28281439
DOI: 10.1128/microbiolspec.TBTB2-0005-2015 -
Microbiology (Reading, England) Sep 2014Adhesion to host cells is a precursor to host colonization and evasion of the host immune response. Conversely, it triggers the induction of the immune response, a... (Review)
Review
Adhesion to host cells is a precursor to host colonization and evasion of the host immune response. Conversely, it triggers the induction of the immune response, a process vital to the host's defence against infection. Adhesins are microbial cell surface molecules or structures that mediate the attachment of the microbe to host cells and thus the host-pathogen interaction. They also play a crucial role in bacterial aggregation and biofilm formation. In this review, we discuss the role of adhesins in the pathogenesis of the aetiological agent of tuberculosis, Mycobacterium tuberculosis. We also provide insight into the structure and characteristics of some of the characterized and putative M. tuberculosis adhesins. Finally, we examine the potential of adhesins as targets for the development of tuberculosis control strategies.
Topics: Adhesins, Bacterial; Antitubercular Agents; Biomarkers; Diagnostic Tests, Routine; Mycobacterium tuberculosis; Virulence Factors
PubMed: 25009234
DOI: 10.1099/mic.0.082206-0