2. Academic Validation
  3. Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin

Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin

  • Angew Chem Int Ed Engl. 2021 Jun 7;60(24):13579-13586. doi: 10.1002/anie.202102224.
Daniel A Wirtz 1,  Kevin C Ludwig 2 3,  Melina Arts 2,  Carina E Marx 2,  Sebastian Krannich 2,  Paul Barac 1,  Stefan Kehraus 1,  Michaele Josten 3 4,  Beate Henrichfreise 2,  Anna Müller 2,  Gabriele M König 1,  Aaron J Peoples 5,  Anthony Nitti 5,  Amy L Spoering 5,  Losee L Ling 5,  Kim Lewis 6,  Max Crüsemann 1,  Tanja Schneider 2
Affiliations

Affiliations

  • 1 Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115, Bonn, Germany.
  • 2 Institute for Pharmaceutical Microbiology, University of Bonn, University Clinic Bonn, Meckenheimer Allee 168, 53115, Bonn, Germany.
  • 3 DZIF, German Center for Infectious Research, partner site Bonn-Cologne, Germany.
  • 4 Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.
  • 5 NovoBiotic Pharmaceuticals, Cambridge, MA, 02138, USA.
  • 6 Department of Biology, Antimicrobial Discovery Center, Northeastern University, Boston, MA, 02115, USA.
PMID: 33768646 DOI: 10.1002/anie.202102224
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.

Keywords

antibiotic; cell wall; cyclodepsipeptide; hydroxylase; lipid II.

Figures
Products