Phylogenetic distance and structural diversity directing a reclassification of glycopeptide antibiotics

Abstract

Antibiotics have been an essential part of modern medicine since their initial discovery. The continuous exploration of new antibiotic candidates remains a necessity given the increasing emergence of resistance to antimicrobial compounds among pathogens. An important group of last-resort antibiotics, the glycopeptide antibiotics (GPAs), have been studied extensively whilst remaining in clinical use even today. GPAs show diversity in both their structures and biosynthetic gene clusters. Reported GPAs have typically comprised seven amino acid residues, which are highly crosslinked and that are decorated with a variable collection of sugar moieties as well as other modifications. These GPAs, which function through non-covalent binding to the bacterial cell wall precursor lipid II, have been classified into four main types based on their structural characteristics. More recently, atypical GPAs have been identified that differ in both their structure and function, and which have been classified as type V GPAs. Given these differences, we have studied the phylogenetics of all gene sequences related to the biosynthesis of the GPAs, where we observe a clear evolutionary diversification of the lipid II binding GPA classes and the so-called type V GPAs. Here, we suggest the adoption of a phylogeny-driven reclassification and separation of classical lipid II binding GPAs from type V GPAs, which we propose to identify instead as glycopeptide- related peptides (GRPs).

糖肽抗生素天然产物研究进展

“…近期研究表明, V 型 GPA 的肽 链骨架不仅局限于七肽, 还包括八肽、九肽以及十肽 [45] , 这样一来对传统 GPA 的分类标准提出 了挑战. 随着越来越多 GPA 生物合成基因簇的发现, Athina Gavriilidou 等人提出从系统发育分析 对 GPA 进行重新分类, 并将传统 GPA 分为糖肽抗生素(I-IV 型, 与 K. C. Nicolaou 分类标准类似) 与糖肽相关肽(Glycopeptide-related peptide, GRP), 然而这一全新分类标准还有待学术界进一步 达成共识 [49] .…”

“…令人振奋的是, V 型 GPA 的发现揭示出了一类全新作用机制的 GPA, 对临床万古霉 素耐药菌株、甲氧西林耐药菌株以及达托霉素耐药菌株均显示出了良好的抑菌活性, 是一类极 具潜力的小分子新药前体化合物 [7] . 全基因组序列分析发现放线菌中存在大量 V 型 GPA 生物合 成基因簇, 这些基因簇不仅编码七肽骨架, 同时还编码八肽、九肽、十肽以及十一肽骨架 [45,49] , 极大地丰富了 GPA 的肽骨架结构多样性, 这些隐藏的 V 型 GPA 的发掘将掀起新一轮 GPA 的发 掘高潮. 然而, V 型 GPA 由于缺少糖苷后修饰, 其抑菌活力与溶解性等理化性质的优化是其在临 床新药开发中必须要解决的问题.…”