摘要
非核糖体肽抗生素包括多粘菌素，万古霉素和teixobactin，其中大部分含有D-氨基酸，对多重耐药细菌非常有效。然而，过度使用抗生素而忽略抗药性的风险无情地导致了耐药菌的广泛出现。因此，阐明对非核糖体肽抗生素产生耐药性的机制对其实施至关重要。在这里我们描述了一个联网相关的基因组挖掘平台，用于将生物合成基因组与生物合成基因簇相关的抗性成分连接起来。通过将这种方法应用于跨越细菌整个结构域的5,585个完整的细菌基因组，随后的化学和酶分析，我们证明了基于D-立体特异性肽酶的水解切割对非核糖体肽抗生素的抗性机制。我们的发现揭示了D-立体特异性肽酶的广泛分布和广谱抗性潜力，提供了对非核糖体肽抗生素的抗生素抗性的潜在早期指示。
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.
https://www.nature.com/articles/s41589-018-0009-4
