MtrA regulation of essential peptidoglycan cleavage in Mycobacterium tuberculosis during infection [MtrA_OE_pH]
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ABSTRACT:
PROVIDER: PRJNA702057 | ENA |
REPOSITORIES: ENA
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Project description:The success of Mycobacterium tuberculosis (Mtb) is largely due to its ability to withstand numerous stresses imposed by host immunity. Here, we present a data-driven model that captures these adaptive mechanisms and reveals the dynamic interplay of host-derived stresses and genome-encoded regulatory programs in Mtb. The model captures the genome-wide distribution of cis-acting gene regulatory elements and the conditional influences of transcription factors at those elements to elicit environment-specific responses. Analysis of transcriptional responses that may be essential for Mtb’s survival in acidic conditions identified regulatory control by the MtrAB two-component signal system. Using genome-wide transcriptomics as well as imaging studies, we have characterized the MtrAB circuit by tunable CRISPRi knockdown in both Mtb and the non-pathogenic organism, M. smegmatis (Msm). These experiments validated the essentiality of MtrA in Mtb, but not Msm. We identified that MtrA regulates multiple enzymes that cleave cell wall peptidoglycan and is required for efficient cell division. Moreover, our results suggest that peptidoglycan cleavage, regulated by MtrA, is required for Mtb to survive intracellular stress. Further, we present MtrA as an attractive drug target, as even weak repression of mtrA results in loss of Mtb viability and completely clears the bacteria with low-dose isoniazid or rifampicin treatment.
2021-07-16 | GSE166805 | GEO
Project description:The success of Mycobacterium tuberculosis (Mtb) is largely due to its ability to withstand numerous stresses imposed by host immunity. Here, we present a data-driven model that captures these adaptive mechanisms and reveals the dynamic interplay of host-derived stresses and genome-encoded regulatory programs in Mtb. The model captures the genome-wide distribution of cis-acting gene regulatory elements and the conditional influences of transcription factors at those elements to elicit environment-specific responses. Analysis of transcriptional responses that may be essential for Mtb’s survival in acidic conditions identified regulatory control by the MtrAB two-component signal system. Using genome-wide transcriptomics as well as imaging studies, we have characterized the MtrAB circuit by tunable CRISPRi knockdown in both Mtb and the non-pathogenic organism, M. smegmatis (Msm). These experiments validated the essentiality of MtrA in Mtb, but not Msm. We identified that MtrA regulates multiple enzymes that cleave cell wall peptidoglycan and is required for efficient cell division. Moreover, our results suggest that peptidoglycan cleavage, regulated by MtrA, is required for Mtb to survive intracellular stress. Further, we present MtrA as an attractive drug target, as even weak repression of mtrA results in loss of Mtb viability and completely clears the bacteria with low-dose isoniazid or rifampicin treatment.
2021-07-16 | GSE166804 | GEO
Project description:MtrA regulation of essential peptidoglycan cleavage in Mycobacterium tuberculosis during infection [mtrA_knockdown]
| PRJNA702058 | ENA
Project description:MtrA regulation of essential peptidoglycan cleavage in Mycobacterium tuberculosis during infection [pH]
| PRJNA694847 | ENA
Project description:The success of Mycobacterium tuberculosis (Mtb) is largely due to its ability to withstand numerous stresses imposed by host immunity. Here, we present a data-driven model that captures these adaptive mechanisms and reveals the dynamic interplay of host-derived stresses and genome-encoded regulatory programs in Mtb. The model captures the genome-wide distribution of cis-acting gene regulatory elements and the conditional influences of transcription factors at those elements to elicit environment-specific responses. Analysis of transcriptional responses that may be essential for Mtb’s survival in acidic conditions identified regulatory control by the MtrAB two-component signal system. This data is a comparison of transcriptional differences (RNA-seq) between low pH (pH 5.6) and neutral pH (pH7) of Mtb
2021-07-16 | GSE165514 | GEO
Project description:Targeting pH-responsive Transcriptional Regulation of Peptidoglycan Cleavage Potentiates Fast Clearance of Mycobacterium tuberculosis with Frontline Antibiotics
| PRJNA702056 | ENA
Project description:PrkA controls peptidoglycan biosynthesis through the essential phosphorylation of ReoM
| PRJEB35110 | ENA
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:Tuberculosis is the leading killer among infectious diseases worldwide. The rise of multi-drug resistance has prompted new approaches for tuberculosis drug development, including inhibition of virulence determinants and of signaling cascades that control many downstream pathways. Here 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 identify these kinases as potentially valuable targets for new anti-tuberculosis drugs. The linked multisystems data provide a valuable resource for future targeted investigations into the pathways regulated by these kinases in the M. tuberculosis cell.
2018-03-09 | PXD008968 | Pride
Project description:The major human pathogen Mycobacterium tuberculosis can survive in the host organism for decades without causing symptoms. A large cohort of Toxin-Antitoxin (TA) modules contribute to this persistence. Of these, 48 TA modules belong to the vapBC (virulence associated protein) gene family. VapC toxins are PIN domain endonucleases that, in Enterobacteria, inhibit translation by site-specific cleavage of initiator tRNA. In contrast, VapC20 of M. tuberculosis inhibits translation by site-specific cleavage of the universally conserved Sarcin-Ricin loop (SRL) in 23S rRNA. Here we identify cleavage targets for 12 VapCs from M. tuberculosis by applying UV-crosslinking and deep sequencing. Remarkably, these VapCs are all endoribo-nucleases that cleave RNA targets that are essential for decoding at the ribosomal A-site. Eleven VapCs cleave specific tRNAs while one exhibits SRL cleavage activity. These findings suggest that multiple vapBC modules contribute to the survival of M. tuberculosis in its human host by reducing the level of translation.
2017-08-14 | GSE85905 | GEO