title: Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase.
abstract: 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 β-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.
authors: College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors: Zhixiang
authors: Z
authors: Xu
authors: College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors: Wei
authors: W
authors: Yin
authors: Center for Drug Design, University of Minnesota, MN 55455, USA.
authors: Leonardo K
authors: LK
authors: Martinelli
authors: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Institute of Infectious Disease and Molecular Medicine and Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa.
authors: Joanna
authors: J
authors: Evans
authors: College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors: Jinglei
authors: J
authors: Chen
authors: College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors: Yang
authors: Y
authors: Yu
authors: Center for Drug Design, University of Minnesota, MN 55455, USA.
authors: Daniel J
authors: DJ
authors: Wilson
authors: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Institute of Infectious Disease and Molecular Medicine and Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa.
authors: Valerie
authors: V
authors: Mizrahi
authors: College of Pharmaceutical Science, Soochow University, Suzhou 215123, China. Electronic address: qiaochunhua@suda.edu.cn.
authors: Chunhua
authors: C
authors: Qiao
authors: Center for Drug Design, University of Minnesota, MN 55455, USA. Electronic address: aldri015@umn.edu.
authors: Courtney C
authors: CC
authors: Aldrich
mesh_terms: D000818:Animals; D003065:Coenzyme A / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D010453:Peptide Synthases; C022318:pantothenate synthetase; D003065:Coenzyme A
keywords: Adenylation; Bisubstrate inhibitor; Coenzyme A; Pantothenate synthetase; Tuberculosis