A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis

Lisa M. Wolfe, Usha Veeraraghavan, Susan Idicula-Thomas, Stephan C Schuerer, Krister Wennerberg, Robert Reynolds, Gurdyal S. Besra, Karen M. Dobos

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis, remains one of the leading causes of death worldwide despite extensive research, directly observed therapy using multidrug regimens, and the widespread use of a vaccine. The majority of patients harbor the bacterium in a state of metabolic dormancy. New drugs with novel modes of action are needed to target essential metabolic pathways in M. tuberculosis; ATP-competitive enzyme inhibitors are one such class. Previous screening efforts for ATP-competitive enzyme inhibitors identified several classes of lead compounds that demonstrated potent anti-mycobacterial efficacy as well as tolerable levels of toxicity in cell culture. In this report, a probe-based chemoproteomic approach was used to selectively profile the M. tuberculosis ATP-binding proteome in normally growing and hypoxic M. tuberculosis. From these studies, 122 ATP-binding proteins were identified in either metabolic state, and roughly 60% of these are reported to be essential for survival in vitro. These data are available through ProteomeXchange with identifier PXD000141. Protein families vital to the survival of the tubercle bacillus during hypoxia emerged from our studies. Specifically, along with members of the DosR regulon, several proteins involved in energy metabolism (Icl/Rv0468 and Mdh/ Rv1240) and lipid biosynthesis (UmaA/Rv0469, DesA1/ Rv0824c, and DesA2/Rv1094) were found to be differentially abundant in hypoxic versus normal growing cultures. These pathways represent a subset of proteins that may be relevant therapeutic targets for development of novel ATP-competitive antibiotics.

Original languageEnglish
Pages (from-to)1644-1660
Number of pages17
JournalMolecular and Cellular Proteomics
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2013

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Proteome
Mycobacterium tuberculosis
Proteomics
Adenosine Triphosphate
Enzyme Inhibitors
Directly Observed Therapy
Lead compounds
Regulon
Proteins
Survival
Biosynthesis
Bacilli
Ports and harbors
Metabolic Networks and Pathways
Cell culture
Bacillus
Energy Metabolism
Toxicity
Cause of Death
Bacteria

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry

Cite this

Wolfe, L. M., Veeraraghavan, U., Idicula-Thomas, S., Schuerer, S. C., Wennerberg, K., Reynolds, R., ... Dobos, K. M. (2013). A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis. Molecular and Cellular Proteomics, 12(6), 1644-1660. https://doi.org/10.1074/mcp.M112.025635

A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis. / Wolfe, Lisa M.; Veeraraghavan, Usha; Idicula-Thomas, Susan; Schuerer, Stephan C; Wennerberg, Krister; Reynolds, Robert; Besra, Gurdyal S.; Dobos, Karen M.

In: Molecular and Cellular Proteomics, Vol. 12, No. 6, 01.06.2013, p. 1644-1660.

Research output: Contribution to journalArticle

Wolfe, LM, Veeraraghavan, U, Idicula-Thomas, S, Schuerer, SC, Wennerberg, K, Reynolds, R, Besra, GS & Dobos, KM 2013, 'A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis', Molecular and Cellular Proteomics, vol. 12, no. 6, pp. 1644-1660. https://doi.org/10.1074/mcp.M112.025635
Wolfe, Lisa M. ; Veeraraghavan, Usha ; Idicula-Thomas, Susan ; Schuerer, Stephan C ; Wennerberg, Krister ; Reynolds, Robert ; Besra, Gurdyal S. ; Dobos, Karen M. / A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis. In: Molecular and Cellular Proteomics. 2013 ; Vol. 12, No. 6. pp. 1644-1660.
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