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Cited by 65Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyInfectious Diseases and Tuberculosis

Multisystem Analysis of Mycobacterium tuberculosis Reveals Kinase-Dependent Remodeling of the Pathogen-Environment Interface

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Carette, Xavier, Platig, John, Young, David C., Helmel, Michaela, Young, Albert T., Wang, Zhe, Potluri, Lakshmi-Prasad, Moody, Cameron Stuver +14 more·2018·mBio
DOI 10.1128/mbio.02333-17PMC PMC5845002
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Abstract

Tuberculosis is the leading killer among infectious diseases worldwide. Increasing multidrug 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 multisystem 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 levels of phosphorylation of many proteins and extensive changes in levels of 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 that these kinases are potentially valuable targets for new antituberculosis drugs. In addition, the data from these linked multisystems provide a valuable resource for future targeted investigations into the pathways regulated by these kinases in the M. tuberculosis cell. IMPORTANCE Tuberculosis is the leading killer among infectious diseases worldwide. Increasing drug resistance threatens efforts to control this epidemic; thus, new antitubercular drugs are urgently needed. We performed an integrated, multisystem analysis of Mycobacterium tuberculosis responses to inhibition of its two essential serine/threonine protein kinases. These kinases allow the bacterium to adapt to its environment by phosphorylating cellular proteins in response to extracellular signals. We identified differentially phosphorylated proteins, downstream changes in levels of specific mRNA and protein abundance, and alterations in the metabolite and lipid content of the cell. These results include changes previously linked to growth arrest and also reveal new roles for these kinases in regulating essential processes, including growth, stress responses, transport of proteins and other molecules, and the structure of the mycobacterial cell envelope. Our multisystem data identify PknA and PknB as promising targets for drug development and provide a valuable resource for future investigation of their functions.

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  • MtrA and PknA or PknB activate transcription of fbpB and fbpA.

    “MtrA and PknA or PknB activate transcription of fbpB and fbpA65.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [65]

    In Results, under “Thr213 phosphorylation disrupts MtrA binding to the fbpB promoter” (page unavailable), the paper describes MtrA as a repressor, not an activator, of fbpB transcription. It reports that PknA/PknB inhibition increases MtrA binding and repression of fbpB. A separate Results passage reports decreased fbpA expression during kinase inhibition but does not establish that MtrA activates fbpA. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

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  • fbpB expression and fbpA expression increase during growth, resulting in high TDM levels and low levels of free mycolic acids.

    “fbpB expression and fbpA expression increase during growth65,106, resulting in high TDM levels and low levels of free mycolic acids14,65,107,108.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [65]

    The Results sections on mycolyl glycolipids and MtrA binding (page not provided) report that kinase inhibition decreases fbpA and fbpB expression or protein abundance, lowers TDM, and raises free mycolates relative to controls. This supports the claimed relationship, but the paper does not show that fbpA and fbpB expression increases over the course of growth; it studies the effects of kinase inhibition, and presents the proposed transfer mechanism as a hypothesis. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Downregulation of PknA and PknB in stasis should also decrease fbpA and fbpB expression.

    “Downregulation of PknA and PknB in stasis59 should also decrease fbpA and fbpB expression65.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [65]

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Cited by

Sorted by citations

Authors
Carette, X., Platig, J., Young, D. C., Helmel, M., Young, A. T., Wang, Z., Potluri, L.-P., Moody, C. S., Zeng, J., Prisic, S., Paulson, J. N., Muntel, J., Madduri, A. V. R., Velarde, J., Mayfield, J. A., Locher, C., Wang, T., Quackenbush, J., Rhee, K. Y., Moody, D. B., Steen, H., & Husson, R. N.
Affiliations
  • Boston Children's Hospital (US)
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
  • Dana-Farber Cancer Institute (US)
  • Weill Cornell Medicine (US)
  • Vertex Pharmaceuticals (United States) (US)
  • Division of Infectious Diseases, Boston Children’s Hospital/Harvard Medical School, Boston, Massachusetts, USA
Corresponding author
Husson, Robert N.
ORCID
Venue
mBio
Publisher
American Society for Microbiology
Published
2018-05-02
Volume
9
Issue
2
ISSN
  • 2150-7511 (ISSN-L)
  • 2161-2129
DOI
10.1128/mbio.02333-17
PMC
PMC5845002
OpenAlex
W2790047349
Cited by
65
References
7
Citations by year
2026: 5 · 2025: 3 · 2024: 7 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 14 · 2019: 13 · 2018: 6
FWCI
7.38
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
HHS | National Institutes of Health (R01AI099204, R01AI116604)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
Keywords
Mycobacterium tuberculosis, PknA, PknB, serine/threonine kinase, kinase inhibitors, tuberculosis drug targets, protein phosphorylation, phosphoproteomics, threonine phosphorylation, peptidoglycan turnover, cell envelope remodeling, cell wall lipids, intracellular metabolites, multidrug resistance, virulence regulation, protein secretion
MeSH terms
Adenosine Triphosphate, Bacterial Proteins, Mycobacterium tuberculosis, Phosphorylation, Signal Transduction, Gene Expression Regulation, Bacterial, Protein Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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