Vancomycin and related glycopeptides are drugs of last resort for the treatment of severe infections caused by Gram-positive bacteria such as Enterococcus species, Staphylococcus aureus, and Clostridium difficile. Vancomycin was long considered immune to resistance due to its bactericidal activity based on binding to the bacterial cell envelope rather than to a protein target as is the case for most antibiotics. However, two types of complex resistance mechanisms, each comprised of a multi-enzyme pathway, emerged and are now widely disseminated in pathogenic species, thus threatening the clinical efficiency of vancomycin. Vancomycin forms an intricate network of hydrogen bonds with the d-Ala-d-Ala region of Lipid II, interfering with the peptidoglycan layer maturation process. Resistance to vancomycin involves degradation of this natural precursor and its replacement with d-Ala-d-lac or d-Ala-d-Ser alternatives to which vancomycin has low affinity. Through extensive research over 30 years after the initial discovery of vancomycin resistance, remarkable progress has been made in molecular understanding of the enzymatic cascades responsible. Progress has been driven by structural studies of the key components of the resistance mechanisms which provided important molecular understanding such as, for example, the ability of this cascade to discriminate between vancomycin sensitive and resistant peptidoglycan precursors. Important structural insights have been also made into the molecular evolution of vancomycin resistance enzymes. Altogether this molecular data can accelerate inhibitor discovery and optimization efforts to reverse vancomycin resistance. Here, we overview our current understanding of this complex resistance mechanism with a focus on the structural and molecular aspects.

中文翻译：

---

万古霉素耐药的分子机制。

万古霉素和相关糖肽是治疗由革兰氏阳性细菌（如肠球菌，金黄色葡萄球菌和艰难梭菌）引起的严重感染的最后手段。长期以来，万古霉素被认为具有抗药性，原因是它的杀菌活性是基于与细菌细胞包膜的结合而不是与大多数抗生素的蛋白质靶标结合。然而，出现了两种类型的复杂抗药性机制，每种机制均由多酶途径组成，现已广泛传播于病原体中，从而威胁了万古霉素的临床疗效。万古霉素与脂质II的d-Ala-d-Ala区域形成复杂的氢键网络，干扰肽聚糖层的成熟过程。对万古霉素的抗性涉及该天然前体的降解及其被万古霉素具有低亲和力的d-Ala-d-lac或d-Ala-d-Ser替代物替代。在最初发现万古霉素耐药性之后的30多年中，通过广泛的研究，在对负责的酶促级联反应的分子理解上取得了显着进展。对抗药性机制关键成分的结构研究推动了进展，该研究提供了重要的分子理解，例如，这种级联区分万古霉素敏感性和抗药性肽聚糖前体的能力。对万古霉素抗性酶的分子进化也有重要的结构见解。总而言之，这种分子数据可以加速抑制剂的发现和优化工作，以逆转万古霉素耐药性。在这里，我们以结构和分子方面为重点，概述了我们目前对这种复杂抗性机制的理解。