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Chembiochem : a European Journal of... Jan 2022Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis, affects millions of people worldwide. Several TB drugs have lost efficacy due to emerging drug... (Review)
Review
Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis, affects millions of people worldwide. Several TB drugs have lost efficacy due to emerging drug resistance and new anti-TB targets are needed. Recent research suggests that indole-3-glycerol phosphate synthase (IGPS) in M. tuberculosis (MtIGPS) could be such a target. IGPS is a (β/α) -barrel enzyme that catalyzes the conversion of 1-(o-carboxyphenylamino)-1-deoxyribulose 5'-phosphate (CdRP) into indole-glycerol-phosphate (IGP) in the bacterial tryptophan biosynthetic pathway. M. tuberculosis over expresses the tryptophan pathway genes during an immune response and inhibition of MtIGPS allows CD4 T-cells to more effectively fight against M. tuberculosis. Here we review the published data on MtIGPS expression, kinetics, mechanism, and inhibition. We also discuss MtIGPS crystal structures and compare them to other IGPS structures to reveal potential structure-function relationships of interest for the purposes of drug design and biocatalyst engineering.
Topics: Amino Acid Sequence; Antitubercular Agents; Biocatalysis; CD4-Positive T-Lymphocytes; Drug Delivery Systems; Humans; Indole-3-Glycerol-Phosphate Synthase; Mycobacterium tuberculosis; Sequence Homology, Amino Acid
PubMed: 34383995
DOI: 10.1002/cbic.202100314 -
PloS One 2021This study was performed to investigate the role of dysglycemia on the genetic diversity of Mycobacterium tuberculosis (MTB) among pulmonary tuberculosis (TB) patients...
This study was performed to investigate the role of dysglycemia on the genetic diversity of Mycobacterium tuberculosis (MTB) among pulmonary tuberculosis (TB) patients to build scientific evidence about the possible mechanisms of TB transmission. MTB isolates obtained of patients affected by pulmonary tuberculosis from health care facilities of North Lima-Peru, were analyzed using whole genome sequencing and 24-locus mycobacterial interspersed repetitive-unit -variable-number tandem repeats (MIRU-VNTR). Subsequently, clinical and epidemiological characteristics were associated with clustering, lineages and comorbid conditions. The analysis carried out 112 pulmonary TB patients from various health centers in North Lima, 17 (15%) had diabetes mellitus (DM) and 33 (29%) had pre-diabetes (PDM). Latin American-Mediterranean, Haarlem and Beijing were the most frequent MTB lineages found in those patients. Previous TB (adjusted odds ratio [aOR] = 3.65; 95%CI: 1.32-17.81), age (aOR = 1.12; 95%CI: 1.03-1.45) and Beijing lineage (aOR = 3.53; 95%CI: 1.08-13.2) were associated with TB-DM comorbidity. Alcoholism (aOR = 2.92; 95%CI: 1.10-8.28), age (aOR = 1.05; 95%CI: 1.03-1.12) and Haarlem lineage (aOR = 2.54; 95%CI: 1.04-6.51) were associated with TB-PDM comorbidity. Beijing and Haarlem lineages were independently associated with TB-DM and TB-PDM comorbidities, respectively. Although these findings may be surprising, we must be cautious to suggest that dysglycemia could be associated with a highly clustering and predisposition of MTB lineages related to a serious impact on the severity of TB disease, which requires further research.
Topics: Adult; Aged; Blood Glucose; Cluster Analysis; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Peru; Phylogeny; Tuberculosis; Young Adult
PubMed: 33507930
DOI: 10.1371/journal.pone.0243184 -
Biochemistry. Biokhimiia Jan 2021Mycobacterium tuberculosis possesses a significant arsenal of strategies to combat immune defense of the host organism. Small noncoding RNAs, which constitute the... (Review)
Review
Mycobacterium tuberculosis possesses a significant arsenal of strategies to combat immune defense of the host organism. Small noncoding RNAs, which constitute the largest group of regulatory RNAs, play an important role in the host-pathogen interactions and represent one of the levels of the regulation of interactions of microbial cells with their environment. The regulatory role of small RNAs in pathogenic bacteria is essential when rapid adaptation to the changing environmental conditions with further synchronization of metabolic reactions are required to ensure microbial survival and infection progression. During the past few years, eight small RNAs from M. tuberculosis have been functionally characterized, and targets for four of them have been identified. Small RNAs from M. tuberculosis and other pathogenic microorganisms were found to be one of the most important functional factors in the adaptive response to changing environmental conditions.
Topics: Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; RNA, Bacterial; RNA, Small Untranslated; Tuberculosis
PubMed: 33827403
DOI: 10.1134/S000629792114008X -
PLoS Neglected Tropical Diseases May 2020Mycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB), is composed of eight subspecies. TB in West Africa, in contrast to other... (Comparative Study)
Comparative Study
BACKGROUND
Mycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB), is composed of eight subspecies. TB in West Africa, in contrast to other geographical regions, is caused by Mycobacterium africanum (MAF) in addition to M. tuberculosis (MTB), with both infections presenting similar symptoms. Nevertheless, MAF is considered to be hypovirulent in comparison with MTB and less likely to progress to active disease. In this study, we asked whether MAF and MTB infected patients possess distinct intestinal microbiomes and characterized how these microbiota communities are affected by anti-tuberculosis therapy (ATT). Additionally, we assessed if the changes in microbiota composition following infection correlate with pathogen induced alterations in host blood-gene expression.
METHODS
A longitudinal, clinical study of MAF infected, MTB infected patients assessed at diagnosis and two months after start of ATT, and healthy, endemic controls was conducted to compare compositions of the fecal microbiome as determined by 16S rRNA sequencing. A blood transcriptome analysis was also performed on a subset of subjects in each group by microarray and the results cross-compared with the same individual's microbiota composition.
FINDINGS
MAF participants have distinct microbiomes compared with MTB patients, displaying decreased diversity and increases in Enterobacteriaceae with respect to healthy participants not observed in the latter patient group. Interestingly, this observed elevation in Enterobacteriaceae positively correlated with enhanced inflammatory gene expression in peripheral blood and was reversed after initiation of ATT.
INTERPRETATION
Our findings indicate that MAF and MTB have distinct associations with the gut microbiome that may be reflective of the differential susceptibility of West Africans to these two co-endemic infections either as biomarkers or as a contributing determinant.
Topics: Adult; Aged; Bacteria; Cohort Studies; Feces; Female; Gastrointestinal Microbiome; Humans; Longitudinal Studies; Male; Middle Aged; Mycobacterium; Mycobacterium tuberculosis; Tuberculosis; Young Adult
PubMed: 32401750
DOI: 10.1371/journal.pntd.0008230 -
Antimicrobial Agents and Chemotherapy Apr 2022We previously identified a series of triazolopyrimidines with antitubercular activity. We determined that Mycobacterium tuberculosis strains with mutations in QcrB, a...
We previously identified a series of triazolopyrimidines with antitubercular activity. We determined that Mycobacterium tuberculosis strains with mutations in QcrB, a subunit of the cytochrome supercomplex, were resistant. A cytochrome oxidase deletion strain was more sensitive to this series. We isolated resistant mutants with mutations in Rv1339. Compounds led to the depletion of intracellular ATP levels and were active against intracellular bacteria, but they did not inhibit human mitochondrial respiration. These data are consistent with triazolopyrimidines acting via inhibition of QcrB.
Topics: Antitubercular Agents; Cytochromes; Electron Transport Complex IV; Humans; Mycobacterium tuberculosis; Respiration
PubMed: 35262374
DOI: 10.1128/aac.02041-21 -
PloS One 2019Human tuberculosis is a life-threatening infection following the inhalation of Mycobacterium tuberculosis, while the closely related bacteria Mycobacterium bovis and...
Human tuberculosis is a life-threatening infection following the inhalation of Mycobacterium tuberculosis, while the closely related bacteria Mycobacterium bovis and Mycobacterium canettii are thought to be transmitted by ingestion. To explore whether M. tuberculosis could also infect individuals by ingestion, male BALBc mice were fed 2 x 106 CFUs of M. tuberculosis Beijing or phosphate-buffered saline as a negative control, over a 28-day experiment. While eight negative control mice remained disease-free, M. tuberculosis was identified in the lymph nodes and lungs of 8/14 mice and in the spleens of 4/14 mice by microscopy, PCR-based detection and culture. Whole-genome sequencing confirmed the identity of the inoculum and the tissue isolates. In these genetically identical mice, the dissemination of M. tuberculosis correlated with the results of the culture detection of four intestinal bacteria. These observations indicate that ingested M. tuberculosis mycobacteria can translocate, notably provoking lymphatic tuberculosis.
Topics: Animals; Bacterial Translocation; Eating; Lung; Lymph Nodes; Male; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Spleen; Tuberculosis
PubMed: 31887178
DOI: 10.1371/journal.pone.0227005 -
Frontiers in Immunology 2020Autophagy, an intracellular catabolic pathway featuring lysosomal degradation, is a central component of the host immune defense against various infections including... (Review)
Review
Autophagy, an intracellular catabolic pathway featuring lysosomal degradation, is a central component of the host immune defense against various infections including (Mtb), the pathogen that causes tuberculosis. Mtb can evade the autophagic defense and drive immunometabolic remodeling of host phagocytes. Co-regulation of the autophagic and metabolic pathways may play a pivotal role in shaping the innate immune defense and inflammation during Mtb infection. Two principal metabolic sensors, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) kinase, function together to control the autophagy and immunometabolism that coordinate the anti-mycobacterial immune defense. Here, we discuss our current understanding of the interplay between autophagy and immunometabolism in terms of combating intracellular Mtb, and how AMPK-mTOR signaling regulates antibacterial autophagy in terms of Mtb infection. We describe several autophagy-targeting agents that promote host antimicrobial defenses by regulating the AMPK-mTOR axis. A better understanding of the crosstalk between immunometabolism and autophagy, both of which are involved in host defense, is crucial for the development of innovative targeted therapies for tuberculosis.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Host-Pathogen Interactions; Humans; Immunity, Innate; Mycobacterium tuberculosis; Signal Transduction; TOR Serine-Threonine Kinases; Tuberculosis
PubMed: 33262773
DOI: 10.3389/fimmu.2020.603951 -
Nature Communications Oct 2023Mycobacterium tuberculosis is protected from antibiotic therapy by a multi-layered hydrophobic cell envelope. Major facilitator superfamily (MFS) transporter Rv1410 and...
Mycobacterium tuberculosis is protected from antibiotic therapy by a multi-layered hydrophobic cell envelope. Major facilitator superfamily (MFS) transporter Rv1410 and the periplasmic lipoprotein LprG are involved in transport of triacylglycerides (TAGs) that seal the mycomembrane. Here, we report a 2.7 Å structure of a mycobacterial Rv1410 homologue, which adopts an outward-facing conformation and exhibits unusual transmembrane helix 11 and 12 extensions that protrude ~20 Å into the periplasm. A small, very hydrophobic cavity suitable for lipid transport is constricted by a functionally important ion-lock likely involved in proton coupling. Combining mutational analyses and MD simulations, we propose that TAGs are extracted from the core of the inner membrane into the central cavity via lateral clefts present in the inward-facing conformation. The functional role of the periplasmic helix extensions is to channel the extracted TAG into the lipid binding pocket of LprG.
Topics: Membrane Transport Proteins; Mycobacterium tuberculosis; Biological Transport; Membranes; Lipids; Protein Conformation
PubMed: 37833269
DOI: 10.1038/s41467-023-42073-0 -
International Journal of Infectious... Feb 2020High accuracy diagnostic screening tests for tuberculosis (TB) are required to improve the diagnosis of both active TB and latent Mycobacterium tuberculosis (MTB)...
OBJECTIVES
High accuracy diagnostic screening tests for tuberculosis (TB) are required to improve the diagnosis of both active TB and latent Mycobacterium tuberculosis (MTB) infection (LTBI). The novel IGRA LIOFeron®TB/LTBI assay was tested and its accuracy was compared to the QuantiFERON®-TB Gold Plus assay.
METHODS
A total of 389 subjects were enrolled in two cohorts and classified as healthy, active TB or LTBI persons. The blood of all the patients was tested with LIOFeron®TB/LTBI assay, containing MTB alanine dehydrogenase, able to differentiate active TB from LTBI diagnosis. The results obtained with both IGRAs, performed on the same 250 samples, were finally compared.
RESULTS
The two assays demonstrated an excellent concordance of their results with patients' diagnosis of MTB infection. ROC analysis for QuantiFERON®-TB Gold Plus showed sensitivity and specificity respectively of 98% and 97% in diagnosing active TB patients and 85% and 94% in diagnosing LTBI subjects. LIOFeron®TB/LTBI assay showed sensitivity and specificity respectively of 90% and 98% in diagnosing active TB patients and 94% and 97% in diagnosing LTBI subjects.
CONCLUSIONS
The two IGRAs displayed the same high accuracy in diagnosing MTB infection/TB disease, and LIOFeron®TB/LTBI assay demonstrated higher sensitivity than QuantiFERON®-TB Gold Plus test in LTBI detection.
Topics: Adult; Aged; Cohort Studies; Diagnostic Tests, Routine; Female; Humans; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; ROC Curve; Sensitivity and Specificity; T-Lymphocytes
PubMed: 31877486
DOI: 10.1016/j.ijid.2019.12.012 -
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