Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

Zhixiang Xu, Wei Yin, Leonardo K. Martinelli, Joanna Evans, Jinglei Chen, Yang Yu, Daniel Wilson, Valerie Mizrahi, Chunhua Qiao, Courtney Aldrich

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1726-1735
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2014

Bibliographical note

Funding Information:
This research was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81072514 , 21002067 to C.Q.), the Ministry of Education Scholarship Fund (The Jiangsu ‘333’ Project to C.Q.), the National Institutes of Health (Grant No. AI070219 to C.C.A.), and the Bill and Melinda Gates Foundation (HIT-TB) Project; to V.M.) and the South African Medical Research Council (to V.M.).

Keywords

  • Adenylation
  • Bisubstrate inhibitor
  • Coenzyme A
  • Pantothenate synthetase
  • Tuberculosis

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