Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin. (7th May 2021)

• Record Type: Journal Article
• Authors: Wirtz, Daniel A.; Ludwig, Kevin C.; Arts, Melina; Marx, Carina E.; Krannich, Sebastian; Barac, Paul; Kehraus, Stefan; Josten, Michaele; Henrichfreise, Beate; Müller, Anna; König, Gabriele M.; Peoples, Aaron J.; Nitti, Anthony; Spoering, Amy L.; Ling, Losee L.; Lewis, Kim; Crüsemann, Max; Schneider, Tanja
• Is Part Of: Angewandte Chemie. Volume 133:Number 24(2021)
• Page Start: 13691
• Page End: 13698
• Publication Date: 2021-05-07
• Subjects: antibiotic -- cell wall -- cyclodepsipeptide -- hydroxylase -- lipid II; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202102224
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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. Abstract : 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.