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Updated: Jun 18, 2026

Synthesis of Masarimycin, a Small Molecule Inhibitor of Gram-Positive Bacterial Growth
Published on: January 7, 2022
Selective inhibitors of bacterial phosphopantothenoylcysteine synthetase
James D Patrone1, Jiangwei Yao, Nicole E Scott
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Abstract:
Bacterial phosphopantothenolycysteine synthetase (PPCS) catalyzes the formation of phosphopantothenoylcysteine (PPC) from (R)-phosphopantothenate, l-cysteine, and cytidine-5'-triphosphate (CTP) and has been shown to be essential for growth and survival. The reaction proceeds through a phosphopantothenoyl cytidylate, mixed anhydride intermediate. Both structural and kinetic characterization studies on PPCS have shown differences in the nucleobase binding site between the bacterial and human enzyme. We report for the first time the design and synthesis of mimics of the phosphopantothenoyl cytidylate, which proved to be potent inhibitors of PPCS. These compounds were evaluated in vitro against PPCS from human and several species of bacteria and showed marked selectivity (up to 1000-fold) toward the bacterial enzymes. A phosphodiester intermediate mimic was the most potent of the compounds synthesized and displayed slow-onset, tight-binding kinetics toward E. faecalis PPCS.
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