Selective inhibitors of bacterial phosphopantothenoylcysteine synthetase.
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.
Patrone
James D
JD
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Yao
Jiangwei
J
Scott
Nicole E
NE
Dotson
Garry D
GD
D015195:Drug Design; D013293:Enterococcus faecalis / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D008968:Molecular Conformation; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013296:Streptococcus pneumoniae / Q000201:enzymology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010755:Organophosphates; D010453:Peptide Synthases; C022374:phosphopantothenoyl-cysteine synthetase