The widespread emergence of antibiotic resistance in pathogens necessitates the development of antibacterial agents inhibiting underexplored targets in bacterial metabolism. One such target is phospho-MurNAc-pentapeptide translocase (MraY), an essential integral membrane enzyme that catalyzes the first committed step of peptidoglycan biosynthesis. MraY has long been considered a promising candidate for antibiotic development in part because it is the target of five classes of naturally occurring nucleoside inhibitors with potent in vivo and in vitro antibacterial activity. Although these inhibitors each have a nucleoside moiety, they vary dramatically in their core structures, and they have different activity properties. Until recently, the structural basis of MraY inhibition was poorly understood. Several recent structures of MraY and its human paralog, GlcNAc-1-P-transferase, have provided insights into MraY inhibition that are consistent with known inhibitor activity data and can inform rational drug design for this important antibiotic target.

病原体中抗生素耐药性的广泛出现需要开发抑制细菌代谢中未充分探索的靶点的抗菌剂。一个这样的目标是磷酸-MurNAc-五肽转位酶 (MraY)，这是一种必不可少的完整膜酶，可催化肽聚糖生物合成的第一个关键步骤。长期以来，MraY 一直被认为是抗生素开发的有希望的候选者，部分原因是它是五类天然存在的核苷抑制剂的靶点，在体内和体外均具有有效作用抗菌活性。尽管这些抑制剂各有一个核苷部分，但它们的核心结构差异很大，并且具有不同的活性特性。直到最近，人们对 MraY 抑制的结构基础知之甚少。MraY 及其人类旁系同源物 GlcNAc-1-P-转移酶的几个最新结构提供了对与已知抑制剂活性数据一致的 MraY 抑制的见解，并可以为这一重要抗生素靶点的合理药物设计提供信息。