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Batson, Sarah; de Chiara, Cesira; Majce, Vita; Lloyd, Adrian J; Gobec, Stanislav; Rea, Dean; Fülöp, Vilmos; Thoroughgood, Christopher W; Simmons, Katie J; Dowson, Christopher G; Fishwick, Colin W G; de Carvalho, Luiz Pedro S; Roper, David I
Nature communications, 12/2017, Volume: 8, Issue: 1Journal Article
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.
