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Nature Reviews. Microbiology Jan 2020Mycobacterium tuberculosis, the leading cause of death due to infection, has a dynamic and immunomodulatory cell envelope. The cell envelope structurally and... (Review)
Review
Mycobacterium tuberculosis, the leading cause of death due to infection, has a dynamic and immunomodulatory cell envelope. The cell envelope structurally and functionally varies across the length of the cell and during the infection process. This variability allows the bacterium to manipulate the human immune system, tolerate antibiotic treatment and adapt to the variable host environment. Much of what we know about the mycobacterial cell envelope has been gleaned from model actinobacterial species, or model conditions such as growth in vitro, in macrophages and in the mouse. In this Review, we combine data from different experimental systems to build a model of the dynamics of the mycobacterial cell envelope across space and time. We describe the regulatory pathways that control metabolism of the cell wall and surface lipids in M. tuberculosis during growth and stasis, and speculate about how this regulation might affect antibiotic susceptibility and interactions with the immune system.
Topics: Adaptive Immunity; Animals; Cell Wall; Drug Tolerance; Host-Pathogen Interactions; Humans; Immune Evasion; Immunity, Innate; Lipid Metabolism; Mycobacterium tuberculosis
PubMed: 31728063
DOI: 10.1038/s41579-019-0273-7 -
Tuberculosis (Edinburgh, Scotland) May 2021Xinjiang is a unique region of Central Asian part of China. It is widely noted for high tuberculosis burden and particularly for growing prevalence of drug resistance....
Xinjiang is a unique region of Central Asian part of China. It is widely noted for high tuberculosis burden and particularly for growing prevalence of drug resistance. Understanding genotypic distribution of Mycobacterium tuberculosis could help clarify unknown causes for the spread of drug-resistant strains. We analyzed 986 M. tuberculosis isolates collected from Xinjiang. Two genotyping schemes, i.e., spoligotyping and multiple-locus variable number tandem repeats (VNTR), were used to determine the phylogenetic lineages and their association with drug-resistances. The M. tuberculosis isolates studied displayed wide distribution of spoligotypic lineages, including Beijing, T, CAS, Ural, LAM, MANU, H, X, EAI, S, Microti, and BOV. The dominant Beijing lineage showed statistical difference from non-Beijing lineages in patients ages (P < 0.001), ethnic groups (P < 0.001) and resistance of three or more drugs (P = 0.008). Further analysis of the year of 2017 subset (n = 257) using VNTR scheme revealed an extremely high discrimination power (Hunter-Gaston discriminatory index = 0.9994). Cluster analysis showed a much lower recent transmission index (7.93%), indicating that the high drug-resistant tuberculosis in this region was mainly caused by reactivation or inappropriate therapy rather than by recent transmission. These data would be valuable for making and implementing policies for improving tuberculosis treatment and care in Xinjiang.
Topics: Adult; Bacterial Typing Techniques; China; Female; Genotype; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Minisatellite Repeats; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult
PubMed: 33713970
DOI: 10.1016/j.tube.2021.102063 -
Microbiology Spectrum Dec 2021Studies involving the pathogenic organism Mycobacterium tuberculosis routinely require advanced biosafety laboratory facilities, which might not be readily available in...
Studies involving the pathogenic organism Mycobacterium tuberculosis routinely require advanced biosafety laboratory facilities, which might not be readily available in rural areas where tuberculosis burdens are high. Attempts to adapt heat inactivation techniques have led to inconsistent conclusions, and the risk of protein denaturation due to extensive heating is impractical for subsequent mass spectrometry (MS)-based protein analyses. In this study, 240 specimens with one or two loops of M. tuberculosis strain H37Rv biomass and specific inactivated solutions were proportionally assigned to six heat inactivation methods in a thermal block at 80°C and 95°C for 20, 30, and 90 min. Twenty untreated specimens served as a positive control, and bacterial growth was followed up for 12 weeks. Our results showed that 90 min of heat inactivation was necessary for samples with two loops of biomass. Further protein extraction and a matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS assay demonstrated adequate scores for bacterial identification (≥1.7), with the highest score achieved in the 80°C/90 min and 95°C/30 min treatment groups. A proteomics study also confidently identified 648 proteins with ∼93% to 96% consistent protein abundances following heating at 95°C for 20, 30, and 90 min. Heat inactivation at 95°C for 90 min yielded the most quantifiable proteins, and a functional analysis revealed proteins located in the ribosomal subunit. In summary, we proposed a heat inactivation method for the M. tuberculosis strain H37Rv and studied the preservation of protein components for subsequent bacterial identification and protein-related assays. Inactivation of Mycobacterium tuberculosis is an important step to guarantee biosafety for subsequent M. tuberculosis identification and related research, notably in areas of endemicity with minimal resources. However, certain biomolecules might be denatured or hydrolyzed because of the harsh inactivation process, and a standardized protocol is yet to be determined. We evaluated distinct heating conditions to report the inactivation efficiency and performed downstream mass spectrometry-based M. tuberculosis identification and proteomics study. The results are important and useful for both basic and clinical M. tuberculosis studies.
Topics: Containment of Biohazards; Drug Resistance, Bacterial; Hot Temperature; Humans; Mass Spectrometry; Microbial Viability; Mycobacterium tuberculosis; Proteome; Proteomics; Tuberculosis
PubMed: 34937194
DOI: 10.1128/spectrum.00716-21 -
Biochimie Jan 2016Gram negative bacteria as well as Gram positive actinobacteria possess the ability to accumulate variable amounts of wax esters (WE) and/or triacylglycerols (TAG) under... (Review)
Review
Gram negative bacteria as well as Gram positive actinobacteria possess the ability to accumulate variable amounts of wax esters (WE) and/or triacylglycerols (TAG) under nitrogen limiting conditions. In recent years many advances have been made to obtain insight into neutral lipid biosynthesis and accumulation in prokaryotes. The clinical and industrial relevance of bacterial WE/TAG significantly promoted basic and applied research in this field. The recent integrated omic studies as well as the functional characterization of diverse genes are contributing to unravel the composition of the WE/TAG-accumulating machinery in bacteria. This will be a valuable data for designing new drugs against bacteria with clinical importance, such as Mycobacterium tuberculosis, or for transferring and optimizing lipid accumulation in bacterial hosts naturally unable to produce such lipids, such as Escherichia coli. In this article, recent investigations addressing WE/TAG biosynthesis and storage in prokaryotes are presented. A comprehensive view of the current knowledge on the different genes/proteins involved in WE/TAG biosynthesis is included.
Topics: Esters; Lipid Metabolism; Mycobacterium tuberculosis; Triglycerides
PubMed: 26343555
DOI: 10.1016/j.biochi.2015.08.016 -
Journal of Immunology (Baltimore, Md. :... Nov 2021In ∼10% of its genome encodes the proline-glutamic acid and proline-proline-glutamic acid (PPE) family of proteins, some of which were recently established to be key... (Review)
Review
In ∼10% of its genome encodes the proline-glutamic acid and proline-proline-glutamic acid (PPE) family of proteins, some of which were recently established to be key players in mycobacterial virulence. PPE2 (Rv0256c) is one among these proteins that we found to have pleiotropic effects during mycobacterial infection. PPE2 weakens the innate immune system by disturbing NO and reactive oxygen species production and myeloid hematopoiesis. We showed that PPE2 is unique for having nuclear localization signal, DNA binding domain, and SRC homology 3 (PXXP) binding domain, which enable it to interfere with the host immune system. Interestingly, PPE2 is a secretary protein, expressed during active tuberculosis (TB) infection, and is involved in facilitating survival of Thus, PPE2 could be a valuable drug target for developing effective therapeutics against TB. In this article, we describe possible roles of PPE2 in TB pathogenesis and the importance of PPE2 as a novel therapeutic target against TB.
Topics: Animals; Antigens, Bacterial; Bacterial Proteins; Humans; Mycobacterium tuberculosis; Virulence
PubMed: 34750243
DOI: 10.4049/jimmunol.2100212 -
Drug Discovery Today Mar 2017TB, caused by the human pathogen Mycobacterium tuberculosis (Mtb), causes more deaths than any other infectious disease. Iron is crucial for Mtb to infect the host and... (Review)
Review
TB, caused by the human pathogen Mycobacterium tuberculosis (Mtb), causes more deaths than any other infectious disease. Iron is crucial for Mtb to infect the host and to sustain infection, with Mtb encoding large numbers of iron-binding proteins. Many of these are hemoproteins with key roles, including defense against oxidative stress, cellular signaling and regulation, host cholesterol metabolism, and respiratory processes. Various heme enzymes in Mtb are validated drug targets and/or products of genes essential for bacterial viability or survival in the host. Here, we review the structure, function, and druggability of key Mtb heme enzymes and strategies used for their inhibition.
Topics: Animals; Antitubercular Agents; Bacterial Proteins; Hemeproteins; Humans; Mycobacterium tuberculosis
PubMed: 27856345
DOI: 10.1016/j.drudis.2016.11.004 -
PloS One 2018Mexico is one of the most important contributors of drug and multidrug-resistant tuberculosis in Latin America; however, knowledge of the genetic diversity of...
BACKGROUND
Mexico is one of the most important contributors of drug and multidrug-resistant tuberculosis in Latin America; however, knowledge of the genetic diversity of drug-resistant tuberculosis isolates is limited.
METHODS
In this study, the genetic structure of 112 Mycobacterium tuberculosis strains from the southeastern Mexico was determined by spoligotyping and 24-loci MIRU-VNTRs.
FINDINGS
The results show eight major lineages, the most of which was T1 (24%), followed by LAM (16%) and H (15%). A total of 29 (25%) isolates were identified as orphan. The most abundant SITs were SIT53/T1 and SIT42/LAM9 with 10 isolates each and SIT50/H3 with eight isolates. Fifty-two spoligotype patterns, twenty-seven clusters and ten clonal complexes were observed, demonstrating an important genetic diversity of drug and multidrug-resistant tuberculosis isolates in circulation and transmission level of these aggravated forms of tuberculosis. Being defined as orphan or as part of an orphan cluster, was a risk factor for multidrug resistant-tuberculosis (OR 2.5, IC 1.05-5.86 and OR 3.3, IC 1-11.03, respectively). Multiple correspondence analyses showed association of some clusters and SITs with specific geographical locations.
CONCLUSIONS
Our study provides one of the most detailed description of the genetic structure of drug and multidrug-resistant tuberculosis strains in southeast Mexico, establishing for the first time a baseline of the genotypes observed in resistant isolates circulating, however further studies are required to better elucidate the genetic structure of tuberculosis in region and the factors that could be participating in their dispersion.
Topics: Adult; Bacterial Typing Techniques; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Genetic Variation; Humans; Male; Mexico; Mycobacterium tuberculosis; Phylogeny; Tuberculosis, Multidrug-Resistant; Young Adult
PubMed: 29543819
DOI: 10.1371/journal.pone.0193626 -
Frontiers in Cellular and Infection... 2018Tuberculosis (TB) is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the... (Review)
Review
Tuberculosis (TB) is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in . Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB), due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of for the development of new therapeutics to meet the immense challenge of global health.
Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Extensively Drug-Resistant Tuberculosis; Genome, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis
PubMed: 29755957
DOI: 10.3389/fcimb.2018.00114 -
Disease Models & Mechanisms Mar 2020Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells....
Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells. Hypoxic lung granuloma in -infected animals present elevated levels of and lactate. Such alterations in the metabolic milieu could influence the outcome of host- interactions. Given the central role of LDHA for tumorigenicity, targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to determine the importance of LDHA for tuberculosis (TB) disease progression and its potential as a target for host-directed therapy. To this end, we orally administered FX11, a known small-molecule NADH-competitive LDHA inhibitor, to -infected C57BL/6J mice and mice with hypoxic necrotizing lung TB lesions. FX11 did not inhibit growth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited replication and onset of necrotic lung lesions in mice. In this model, isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant bacterial subpopulation. However, adjunct FX11 treatment corrected this adverse effect and resulted in sustained bactericidal activity of INH against As a limitation, LDHA inhibition as an underlying cause of FX11-mediated effect could not be established as the on-target effect of FX11 was unconfirmed. Nevertheless, this proof-of-concept study encourages further investigation on the underlying mechanisms of LDHA inhibition and its significance in TB pathogenesis.
Topics: Animals; Disease Models, Animal; Female; Host-Pathogen Interactions; Isoniazid; Mice, Inbred C57BL; Mycobacterium tuberculosis; Naphthalenes
PubMed: 32034005
DOI: 10.1242/dmm.041954 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Aug 2018Currently, there are many studies on the mechanism of antibiotic resistance in Mycobacterium tuberculosis (Mtb), but there are few studies on its regulatory mechanism.... (Review)
Review
Currently, there are many studies on the mechanism of antibiotic resistance in Mycobacterium tuberculosis (Mtb), but there are few studies on its regulatory mechanism. Post-translational modifications (PTMs) have been recognized for their important role in controlling cellular dynamics such as metabolism and stress response, but the relationship between PTMs and antibiotic resistance gradually attracted the attention of researchers. Here, we summarize the definition of PTMs, and the mechanisms of antibiotic resistance in M. tuberculosis and discuss how PTMs are involved in antibiotic resistance, in order to provide a new breakthrough for the development of new anti-Ttb drugs.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Mycobacterium tuberculosis; Protein Processing, Post-Translational
PubMed: 30152213
DOI: 10.13345/j.cjb.170530