A high-throughput screen against pantothenate synthetase (PanC) identifies 3-biphenyl-4-cyanopyrrole-2-carboxylic acids as a new class of inhibitor with activity against Mycobacterium tuberculosis.
The enzyme pantothenate synthetase, PanC, is an attractive drug target in Mycobacterium tuberculosis. It is essential for the in vitro growth of M. tuberculosis and for survival of the bacteria in the mouse model of infection. PanC is absent from mammals. We developed an enzyme-based assay to identify inhibitors of PanC, optimized it for high-throughput screening, and tested a large and diverse library of compounds for activity. Two compounds belonging to the same chemical class of 3-biphenyl-4- cyanopyrrole-2-carboxylic acids had activity against the purified recombinant protein, and also inhibited growth of live M. tuberculosis in manner consistent with PanC inhibition. Thus we have identified a new class of PanC inhibitors with whole cell activity that can be further developed.
Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
Anuradha
A
Kumar
Allen
A
Casey
Joshua
J
Odingo
Edward A
EA
Kesicki
Garth
G
Abrahams
Michal
M
Vieth
Thierry
T
Masquelin
Valerie
V
Mizrahi
Philip A
PA
Hipskind
David R
DR
Sherman
Tanya
T
Parish
D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy* / Q000201:enzymology; D014709:Vero Cells
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D010453:Peptide Synthases; C022318:pantothenate synthetase