Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin
| Autor: | Max Crüsemann, Daniel A. Wirtz, Aaron J. Peoples, Anthony Nitti, Gabriele M. König, Michaele Josten, Beate Henrichfreise, Kevin C Ludwig, Stefan Kehraus, Carina E Marx, Sebastian Krannich, Melina Arts, Kim Lewis, Paul Barac, Amy Spoering, Tanja Schneider, Losee L Ling, Anna Müller |
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| Rok vydání: | 2021 |
| Předmět: |
hydroxylase
Teixobactin cyclodepsipeptide Microbial Sensitivity Tests Gram-Positive Bacteria 010402 general chemistry Biochemistry 01 natural sciences Catalysis Bacterial cell structure Mixed Function Oxygenases Hydroxylation Cell wall chemistry.chemical_compound Biosynthesis Cell Wall antibiotic Gram-Negative Bacteria Gene cluster Peptide Synthases Lipid II 010405 organic chemistry Chemistry Communication lipid II General Medicine General Chemistry Communications In vitro Anti-Bacterial Agents 0104 chemical sciences Lysobacter Multigene Family Antimicrobial Cationic Peptides |
| Zdroj: | Angewandte Chemie (International Ed. in English) |
| ISSN: | 1521-3773 1433-7851 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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