Mycobacterium tuberculosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA251986 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1363500.fastq.gz | Fastqsanger.gz | |||
| SRR1363501.fastq.gz | Fastqsanger.gz | |||
| SRR1363502.fastq.gz | Fastqsanger.gz | |||
| SRR1363503.fastq.gz | Fastqsanger.gz | |||
| SRR1363504.fastq.gz | Fastqsanger.gz |
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Project description:Virulence effectors secreted by Mycobacterium tuberculosis (Mtb) help subvert host immune mechanisms and, therefore, are critical for establishing infection and pathogenesis. However, knowledge in terms of signaling mechanisms that modulate the secretion of virulence factors is sparse. We performed high-throughput secretome, phosphoproteome, and phospho-secretome analysis of Mtb. We combined the analysis with empirical validations to show regulation of mycobacterial secretion through protein phosphorylation. System level PPI network analysis superimposed with the secretome, phosphoproteome, and phospho-secretome profile revealed an intricate relationship between phosphorylation and secretion. At the core of the network was a key virulence factor CFP10. We identified PknA to be the kinase responsible for phosphorylating CFP10. Using genetic tools, we show that phosphomimetic mutation of CFP10 negatively regulates the secretion of virulence mediator ESAT6. Significantly, the dynamics of CFP10 phosphorylation strongly influenced bacterial virulence and survival within macrophages and mice. Together, the results show that the dynamic phosphorylation status of the secretory protein CFP10 regulates the secretion of virulence factors and impacts virulence.
2023-09-22 | PXD045586 | Pride
Project description:Mycobacterium tuberculosis (Mtb) depends on protein secretion systems for intracellular survival and virulence. The major virulence determinant and ESX-1 dependent effector protein EsxA causes tissue damage and necrosis which promotes spread and dissemination of the bacterium. We developed a fibroblast survival assay (FSA) that exploits this phenotype by selecting for molecules that protect host cells from Mtb-induced lysis. Hit compounds identified in this high-throughput screen blocked the secretion of EsxA thus promoting phagosome maturation which led to substantially reduced bacterial burden in activated macrophages. Target identification studies performed on these drugs led to discovery of a benzothiophene containing histidine kinase inhibitor and a benzyloxybenzylidine hydrazine compound affecting mycobacterial metal ion homeostasis which enabled us to reveal zinc stress as a signal for EsxA secretion. Collectively, this novel drug screening approach can help to tackle the mounting problem of antibiotic-resistant mycobacteria by largely extending the target spectrum of small molecule libraries.
2015-05-15 | GSE58314 | GEO
Project description:Tuberculosis (TB) which is one of the deadliest infectious disease worldwide, is caused by the inhalation of the pathogenic bacteria Mycobacterium tuberculosis. Since many years now, the emergence of multiple (MDR), extensively (XDR) and totally (TDR) drug resistant strains amplifies the incidences of TB resulting in failure of treatment and death. However, no new TB drug classes have been developed or approved for drug susceptible TB since the current 6-month four-drug combination was introduced in the 1970s. Most of the promising new molecules in development are either repurposed drug compounds or new derivatives of known anti-mycobacterial drugs that mainly target the bacteria cell wall biosynthesis. It is now acknowledged that microbial lipolytic enzymes are involved in bacterial growth, cell wall biosynthesis, carbon sources management and virulence during infections by M. tuberculosis. Although no drug is reported to target specifically enzymes involved in mycobacterial intracellular lipid metabolism; our results have clearly shown that mycobacterial enzymes can be potential therapeutic targets. Consequently, specific inhibitors of such enzymes might turn out to be valuable anti-tuberculous agents. We previously reported that the Cyclophostin & Cyclipostins (CyC) analogs are a new family of potent antimycobacterial molecules which react specifically and covalently with (Ser/Cys)-based enzymes. Competitive ABPP approach with CyC17-pretreated M. tb lysate and the ActivX Desthiobiotin-FP activity-based probe (ABP) allowed identifying 23 distinct proteins as potential targets of this inhibitor, that were all (Ser/Cys)-based enzymes, most of them participating in M. tb lipid metabolism and cell wall biosynthesis. However, this approach for target identification in cell lysates is mostly indirect with the risk of false positive hits, and cannot be applied in vivo for various technical reasons, the main one being the need for a large number of compounds and cells. To overcome these issues, we report here the synthesis of new CyC alkyne-containing inhibitors (i.e., CyCyne) analogous to CyC17, and their use for the direct fishing of target proteins in living M. tb via bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP) strategy. In particular, we further explore and validate, through a combination of biochemical and structural approaches, the specificity of inhibition of the HsaD activity by the CyC analogs.
2022-09-20 | PXD034921 | Pride
Project description:A cell-based phenotypic screen for inhibitors of biofilm formation in Mycobacterium tuberculosis (Mtb) identified the small molecule TCA1, which has bactericidal activity against both drug susceptible and drug resistant Mtb, and synergizes with rifampicin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition, TCA1 has bactericidal activity against non-replicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models, both alone and in combination with INH or RIF. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb dormancy and drug tolerance. Mutagenesis and affinity-based methods identified DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as the targets responsible for TCA1M-bM-^@M-^Ys activity. These in vitro and in vivo results indicate that TCA1functions by a novel mechanism and suggest that it may be the first product of a promising new approach for the development of anti-tuberculosis drugs. Transcriptional profile of TCA1-treated cells relative to DMSO-treated control. Three biological replicates, third is a dye flip.
2013-05-24 | E-GEOD-42151 | biostudies-arrayexpress
Project description:The result validated the connections between mutations, gene expression and mycobacterial pathogenicity, and identified new possible virulence-associated pathways in M. tuberculosis.
2022-07-13 | GSE203662 | GEO
Project description:A cell-based phenotypic screen for inhibitors of biofilm formation in Mycobacterium tuberculosis (Mtb) identified the small molecule TCA1, which has bactericidal activity against both drug susceptible and drug resistant Mtb, and synergizes with rifampicin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition, TCA1 has bactericidal activity against non-replicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models, both alone and in combination with INH or RIF. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb dormancy and drug tolerance. Mutagenesis and affinity-based methods identified DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as the targets responsible for TCA1’s activity. These in vitro and in vivo results indicate that TCA1functions by a novel mechanism and suggest that it may be the first product of a promising new approach for the development of anti-tuberculosis drugs.
2013-05-24 | GSE42151 | GEO
Project description:Tuberculosis is the leading killer among infectious diseases worldwide. Increasing multi-drug resistance has prompted new approaches for tuberculosis drug development, including targeted inhibition of virulence determinants and of signaling cascades that control many downstream pathways. We used a multisystems approach to determine the effects of a potent small molecule inhibitor of the essential Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB. We observed differential phosphorylation of many proteins and extensive changes in gene expression, protein abundance, cell wall lipids and intracellular metabolites. The patterns of these changes indicate regulation by PknA and PknB of several pathways required for cell growth, including ATP synthesis, DNA synthesis and translation. These data also highlight effects on pathways for remodeling of the mycobacterial cell envelope via control of peptidoglycan turnover, lipid content, a SigE-mediated envelope stress response, transmembrane transport systems, and protein secretion systems. Integrated analysis of phosphoproteins, transcripts, proteins, and lipids identified an unexpected pathway whereby threonine phosphorylation of the essential response regulator MtrA decreases its DNA binding activity. Inhibition of this phosphorylation is linked to decreased expression of genes for peptidoglycan turnover, and of genes for mycolyl transferases, with concomitant changes in mycolates and glycolipids in the cell envelope. These findings reveal novel roles for PknA and PknB in regulating multiple essential cell functions and confirm these kinases as potentially valuable targets for new anti-tuberculosis drugs. In addition, these linked multisystems data provide a valuable resource for future targeted investigations into the pathways regulated by these kinases in the M. tuberculosis cell.
2018-03-08 | GSE110508 | GEO
Project description:Mycobacterium tuberculosis relies on the ESX-1 secretion system for survival, multiplication in and escape from macrophages. In this work we investigate the role of the EspB protein, encoded within the esx-1 gene cluster, in virulence and ESX-1 substrate secretion in M. tuberculosis H37Rv. Genetic, proteomic and immunological data show that, contrary to previous reports, an espB knock-out mutant is only partially attenuated in ex vivo infection models, where EsxA, EsxB and EspC antigen presentation is not affected, and secretes the major virulence factor EsxA. Additionally, we demonstrate that EspB does not require an intact and functional ESX-1 apparatus for being secreted in H37Rv and in M. bovis BCG, as opposed to other strains such as CDC1551 and Erdman, thereby suggesting that other ESX systems may be involved in the process. Overall our findings highlight unexplored differences in the secretion profiles of various mycobacterial strains and underscore the plasticity of ESX-dependent secretion in mycobacteria.
2021-09-24 | PXD016565 | Pride
Project description:We report here lead optimisation efforts of a new series of cytochrome bc1 oxidase inhibitors, the quinazoline derivatives. Four derivatives showed mild to no cytotoxicity as potent in vitro and ex vivo activity in infected THP-1 macrophages against M. tuberculosis. Isolation of resistant mutants to one of the derivatives in M. tuberculosis revealed mutations in both QcrA and QcrB of the cytochrome bc1 oxidase, one of two terminal oxidases of the mycobacterial electron transport chain. Cross-resistance studies, transcriptomic analyses and bioenergetics flux assays provide further evidence of the cytochrome bc1 as the target of the quinazolines compounds. The transcriptomic and bioenergetic profiles obtained when M. tuberculosis was treated with 11626252 are similar to transcriptomic and respiratory signatures of other cytochrome bc1 oxidase inhibitors.
2019-08-01 | GSE119158 | GEO
Project description:Staphylococcus aureus is a major bacterial pathogen that invades and damages host tissue by the expression of devastating toxins. We here performed a phenotypic screen of 35 molecules that were structurally inspired by previous hydroxyamide-based S. aureus virulence inhibitors compiled from commercial sources or designed and synthesized de novo. One of the most potent compounds, AV73, did not only reduce hemolytic alpha-hemolysin expression in S. aureus but also impeded in vitro biofilm formation. The effect of AV73 on bacterial proteomes and extracellular protein levels were analyzed by quantitative proteomics and revealed a significant down-regulation of major virulence and biofilm promoting proteins. To elucidate the mode of action of AV73, target identification was performed using affinity-based protein profiling (AfBPP).
2018-03-05 | PXD008067 | Pride