Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin.
Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin.
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DOI：
10.1002/anie.202102224
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发表时间：
2021-06-07
期刊：
影响因子：
--
通讯作者：
Schneider T
中科院分区：
文献类型：
--
作者：
Wirtz DA;Ludwig KC;Arts M;Marx CE;Krannich S;Barac P;Kehraus S;Josten M;Henrichfreise B;Müller A;König GM;Peoples AJ;Nitti A;Spoering AL;Ling LL;Lewis K;Crüsemann M;Schneider T
hyppeptin是一种由Lysobacter sp. K5869生产的环沉积肽抗生素，通过iChip技术从环境样品中分离出来，专门用于培养以前未培养的微生物。hyppeptin与teixobactin具有相同的结构特征，并且对广谱的革兰氏阳性病原体具有有效的活性。通过全面的体内和体外分析，我们发现hyppeptin通过与多种含焦磷酸去戊烯基的生物合成中间体结合，形成一个2:1的化学计量复合物，从而阻断细菌细胞壁的生物合成。在体外并不容易产生对低肽的耐药性。低肽生物合成基因簇（BGC）的分析支持了该八肽的合成模型。在BGC中，鉴定并表征了两种羟化酶，当与肽基载体蛋白结合时，它们负责四种构建块的立体选择性β -羟化。体外羟基化实验证实了生物合成假说，并提出了hyppeptin的精细结构。非核糖体肽hyppeptin通过结合脂质II阻止革兰氏阳性细菌的细胞壁生物合成。即使在指数生长的后期，它也能杀死病原体，而不会产生明显的耐药性。体外生物合成研究，结合生物信息学和核磁共振分析，提出了一个精细的结构。
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. The nonribosomal peptide hypeptin blocks cell wall biosynthesis of gram‐positive bacteria by binding to lipid II. It kills pathogens even in late exponential growth phase without detectable development of resistance. Investigation of the biosynthesis in vitro, combined with bioinformatic and NMR analyses led to the proposal of a refined structure.
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DOI：
10.2174/1568005014606116
发表时间：
2001-08-01
期刊：
Current Drug Targets - Infectious Disorders
影响因子：
--
作者：
Ha, S.;Gross, B.;Walker, S.
通讯作者：
Walker, S.
影响因子：
16.6
作者：
Hermes C;Richarz R;Wirtz DA;Patt J;Hanke W;Kehraus S;Voß JH;Küppers J;Ohbayashi T;Namasivayam V;Alenfelder J;Inoue A;Mergaert P;Gütschow M;Müller CE;Kostenis E;König GM;Crüsemann M
通讯作者：
Crüsemann M
影响因子：
4.8
作者：
Miller, Bradley R.;Drake, Eric J.;Gulick, Andrew M.
通讯作者：
Gulick, Andrew M.
影响因子：
3.6
作者：
Radeck, Jara;Gebhard, Susanne;Fritz, Georg
通讯作者：
Fritz, Georg
影响因子：
4
作者：
Kaniusaite, Milda;Goode, Robert J. A.;Cryle, Max J.
通讯作者：
Cryle, Max J.