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

Mol Cell Proteomics. 2013 Jun;12(6):1644-60. doi: 10.1074/mcp.M112.025635. Epub 2013 Mar 5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / antagonists & inhibitors
  • Adenosine Triphosphate / chemistry*
  • Adenosine Triphosphate / metabolism
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / genetics
  • Bacterial Proteins / isolation & purification*
  • Bacterial Proteins / metabolism
  • Binding, Competitive
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / isolation & purification*
  • Carrier Proteins / metabolism
  • Culture Media
  • DNA-Binding Proteins
  • Gene Expression Regulation, Bacterial / drug effects*
  • Isocitrate Lyase / genetics
  • Isocitrate Lyase / metabolism
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / metabolism
  • Oxygen / metabolism
  • Oxygen / pharmacology
  • Peptides / chemistry
  • Peptides / pharmacology
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / isolation & purification
  • Protein Isoforms / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Proteome / antagonists & inhibitors
  • Proteome / chemistry*
  • Proteome / genetics
  • Proteomics / methods*
  • Signal Transduction


  • ATP-binding protein, bacteria
  • Antitubercular Agents
  • Bacterial Proteins
  • Carrier Proteins
  • Culture Media
  • DNA-Binding Proteins
  • DosR protein, Mycobacterium tuberculosis
  • Peptides
  • Protein Isoforms
  • Proteome
  • Adenosine Triphosphate
  • Protein Kinases
  • icl protein, Mycobacterium
  • Isocitrate Lyase
  • Oxygen