1. Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine.
- Author
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Batson S, de Chiara C, Majce V, Lloyd AJ, Gobec S, Rea D, Fülöp V, Thoroughgood CW, Simmons KJ, Dowson CG, Fishwick CWG, de Carvalho LPS, and Roper DI
- Subjects
- Alanine Racemase, Antibiotics, Antitubercular metabolism, Cycloserine metabolism, Escherichia coli, Escherichia coli Proteins antagonists & inhibitors, Escherichia coli Proteins drug effects, Peptide Synthases drug effects, Phosphorylation, Antibiotics, Antitubercular pharmacology, Cycloserine pharmacology, Peptide Synthases antagonists & inhibitors
- Abstract
D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, chemical and mechanistic studies here we show that the inhibition of D-alanine:D-alanine ligase by the antibiotic D-cycloserine proceeds via a distinct phosphorylated form of the drug. This mechanistic insight reveals a bimodal mechanism of action for a single antibiotic on different enzyme targets and has significance for the design of future inhibitor molecules based on this chemical structure.
- Published
- 2017
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