Department of Ocean Science and Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Nat Chem Biol. 2018 Apr;14(4):381-387. doi: 10.1038/s41589-018-0009-4. Epub 2018 Feb 26.
Nonribosomal peptide antibiotics, including polymyxin, vancomycin, and teixobactin, most of which contain D-amino acids, are highly effective against multidrug-resistant bacteria. However, overusing antibiotics while ignoring the risk of resistance arising has inexorably led to widespread emergence of resistant bacteria. Therefore, elucidation of the emerging mechanisms of resistance to nonribosomal peptide antibiotics is critical to their implementation. Here we describe a networking-associated genome-mining platform for linking biosynthetic building blocks to resistance components associated with biosynthetic gene clusters. By applying this approach to 5,585 complete bacterial genomes spanning the entire domain of bacteria, with subsequent chemical and enzymatic analyses, we demonstrate a mechanism of resistance toward nonribosomal peptide antibiotics that is based on hydrolytic cleavage by D-stereospecific peptidases. Our finding reveals both the widespread distribution and broad-spectrum resistance potential of D-stereospecific peptidases, providing a potential early indicator of antibiotic resistance to nonribosomal peptide antibiotics.
非核糖体肽类抗生素，包括多黏菌素、万古霉素和泰妙菌素，其中大多数都含有 D-氨基酸，对多药耐药菌具有高度的有效性。然而，在忽视耐药性产生风险的情况下过度使用抗生素，不可避免地导致了耐药菌的广泛出现。因此，阐明非核糖体肽类抗生素耐药性产生的新机制对于它们的应用至关重要。在这里，我们描述了一个与网络相关的基因组挖掘平台，用于将生物合成的构建块与生物合成基因簇相关的抗性成分联系起来。通过将这种方法应用于涵盖整个细菌领域的 5585 个完整细菌基因组，并进行随后的化学和酶分析，我们证明了一种基于 D-立体特异性肽酶水解裂解的非核糖体肽类抗生素抗性机制。我们的发现揭示了 D-立体特异性肽酶的广泛分布和广谱耐药潜力，为非核糖体肽类抗生素的耐药性提供了一个潜在的早期指标。
