Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115, Bonn, Germany.
Institute for Pharmaceutical Microbiology, University of Bonn, University Clinic Bonn, Meckenheimer Allee 168, 53115, Bonn, Germany.
Angew Chem Int Ed Engl. 2021 Jun 7;60(24):13579-13586. doi: 10.1002/anie.202102224. Epub 2021 May 7.
Hypeptin is a cyclodepsipeptide antibiotic produced by Lysobacter sp. K5869, isolated from an environmental sample by the iChip technology, dedicated to the cultivation of previously uncultured microorganisms. Hypeptin shares structural features with teixobactin and exhibits potent activity against a broad spectrum of gram-positive pathogens. Using comprehensive in vivo and in vitro analyses, we show that hypeptin blocks bacterial cell wall biosynthesis by binding to multiple undecaprenyl pyrophosphate-containing biosynthesis intermediates, forming a stoichiometric 2:1 complex. Resistance to hypeptin did not readily develop in vitro. Analysis of the hypeptin biosynthetic gene cluster (BGC) supported a model for the synthesis of the octapeptide. Within the BGC, two hydroxylases were identified and characterized, responsible for the stereoselective β-hydroxylation of four building blocks when bound to peptidyl carrier proteins. In vitro hydroxylation assays corroborate the biosynthetic hypothesis and lead to the proposal of a refined structure for hypeptin.
海普汀是一种环二肽抗生素，由 Lysobacter sp. K5869 产生，该菌株是通过 iChip 技术从环境样本中分离出来的，专门用于培养以前无法培养的微生物。海普汀与泰妙菌素具有结构特征，对广谱革兰氏阳性病原体具有强大的活性。通过全面的体内和体外分析，我们表明海普汀通过与多种含有十一烯基焦磷酸的生物合成中间体结合，形成化学计量比为 2:1 的复合物，从而阻断细菌细胞壁的生物合成。海普汀在体外不易产生耐药性。对海普汀生物合成基因簇 (BGC) 的分析支持了八肽合成的模型。在 BGC 中，鉴定并表征了两个羟化酶，当与肽基载体蛋白结合时，负责四个构建块的立体选择性β-羟化。体外羟化测定证实了生物合成假说，并提出了海普汀的改进结构。
