Abstract
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.
Highlights
One third of the human population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) [1]
Pantothenate is a key precursor for the biosynthesis of coenzyme A (CoA) and acyl carrier protein (ACP), critical components of fatty acid synthesis
PanC is absent in mammals, who scavenge pantothenate from their diet using pantothenate permease [7,8], of which there is no homolog in M. tuberculosis
Summary
One third of the human population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) [1]. A hallmark of M. tuberculosis is its lipid-rich cell wall, which is an essential element of intracellular survival and pathogenicity, and is thought to contribute to the difficulty of effectively delivering antimicrobial agents into the cell. The significance of this lipid-rich cell wall is underscored by the large number of genes (,250) encoding enzymes in fatty acid metabolism present in the M. tuberculosis genome [2], making this pathway a promising target for new antibacterial drug discovery. This suggests the potential for developing drugs that do not have cross-reactive toxicity to homologs in the host, and makes PanC an attractive drug target in M. tuberculosis
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