TY - JOUR
T1 - A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis
AU - Wolfe, Lisa M
AU - Veeraraghavan, Usha
AU - Idicula-Thomas, Susan
AU - Schürer, Stephan
AU - Wennerberg, Krister
AU - Reynolds, Robert
AU - Besra, Gurdyal S
AU - Dobos, Karen M
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - Adenosine Triphosphate/antagonists & inhibitors
KW - Antitubercular Agents/chemistry
KW - Bacterial Proteins/antagonists & inhibitors
KW - Binding, Competitive
KW - Carrier Proteins/antagonists & inhibitors
KW - Culture Media
KW - Gene Expression Regulation, Bacterial/drug effects
KW - Isocitrate Lyase/genetics
KW - Mycobacterium tuberculosis/drug effects
KW - Oxygen/metabolism
KW - Peptides/chemistry
KW - Protein Binding
KW - Protein Interaction Mapping
KW - Protein Isoforms/antagonists & inhibitors
KW - Protein Kinases/genetics
KW - Proteome/antagonists & inhibitors
KW - Proteomics/methods
KW - Signal Transduction
U2 - 10.1074/mcp.m112.025635
DO - 10.1074/mcp.m112.025635
M3 - Journal article
C2 - 23462205
SN - 1535-9476
VL - 12
SP - 1644
EP - 1660
JO - Molecular and Cellular Proteomics
JF - Molecular and Cellular Proteomics
IS - 6
ER -
