School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, NW1 1AT, London, UK.
Nat Commun. 2017 Dec 5;8(1):1939. doi: 10.1038/s41467-017-02118-7.
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.
D-环丝氨酸是一种抗生素，它针对细菌细胞壁肽聚糖生物合成酶的顺序：丙氨酸消旋酶和 D-丙氨酸：D-丙氨酸连接酶。通过结构、化学和机制研究的结合，我们在这里表明，抗生素 D-环丝氨酸对 D-丙氨酸：D-丙氨酸连接酶的抑制作用是通过药物的一种独特的磷酸化形式进行的。这种机制上的见解揭示了一种单一抗生素对不同酶靶标作用的双重模式机制，并且对于基于该化学结构设计未来的抑制剂分子具有重要意义。
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