Institut de Biologie Structurale (IBS), Université Grenoble Alpes, 6 rue Jules Horowitz, 38027, Grenoble, France; Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Grenoble, France; Centre National de la Recherche Scientifique (CNRS), UMR 5075, Grenoble, France; Bijvoet Center for Biomolecular Research, Department of Biochemistry of Membranes, Utrecht University, Utrecht, The Netherlands.
Protein Sci. 2014 Mar;23(3):243-59. doi: 10.1002/pro.2414. Epub 2014 Jan 17.
Peptidoglycan is the main component of the bacterial cell wall. It is a complex, three-dimensional mesh that surrounds the entire cell and is composed of strands of alternating glycan units crosslinked by short peptides. Its biosynthetic machinery has been, for the past five decades, a preferred target for the discovery of antibacterials. Synthesis of the peptidoglycan occurs sequentially within three cellular compartments (cytoplasm, membrane, and periplasm), and inhibitors of proteins that catalyze each stage have been identified, although not all are applicable for clinical use. A number of these antimicrobials, however, have been rendered inactive by resistance mechanisms. The employment of structural biology techniques has been instrumental in the understanding of such processes, as well as the development of strategies to overcome them. This review provides an overview of resistance mechanisms developed toward antibiotics that target bacterial cell wall precursors and its biosynthetic machinery. Strategies toward the development of novel inhibitors that could overcome resistance are also discussed.
肽聚糖是细菌细胞壁的主要成分。它是一个复杂的三维网格，环绕着整个细胞，由交替的聚糖链组成，通过短肽交联。在过去的五十年中，其生物合成机制一直是发现抗菌药物的首选目标。肽聚糖的合成在三个细胞区室（细胞质、膜和周质）中依次进行，已经鉴定出催化每个阶段的蛋白质的抑制剂，尽管并非所有抑制剂都适用于临床应用。然而，许多这些抗生素已经被耐药机制所削弱。结构生物学技术的应用对于理解这些过程以及开发克服这些过程的策略非常重要。本综述提供了对抗生素的耐药机制的概述，这些抗生素针对细菌细胞壁前体及其生物合成机制。还讨论了开发可以克服耐药性的新型抑制剂的策略。
