期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 5, 页码 1726-1735出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.01.017
关键词
Pantothenate synthetase; Tuberculosis; Bisubstrate inhibitor; Adenylation; Coenzyme A
资金
- National Natural Science Foundation of China [81072514, 21002067]
- Ministry of Education Scholarship Fund (The Jiangsu '333' Project)
- National Institutes of Health [AI070219]
- Bill and Melinda Gates Foundation (HIT-TB) Project
- South African Medical Research Council
The biosynthesis of pantothenate, the core of coenzyme A (CoA), has been considered an attractive target for the development of antimicrobial agents since this pathway is essential in prokaryotes, but absent in mammals. Pantothenate synthetase, encoded by the gene panC, catalyzes the final condensation of pantoic acid with beta-alanine to afford pantothenate via an intermediate pantoyl adenylate. We describe the synthesis and biochemical characterization of five PanC inhibitors that mimic the intermediate pantoyl adenylate. These inhibitors are competitive inhibitors with respect to pantoic acid and possess submicromolar to micromolar inhibition constants. The observed SAR is rationalized through molecular docking studies based on the reported co-crystal structure of 1a with PanC. Finally, whole cell activity is assessed against wild-type Mtb as well as a PanC knockdown strain where PanC is depleted to less than 5% of wild-type levels. (C) 2014 Elsevier Ltd. All rights reserved.
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