2. Academic Validation
  3. Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics

Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics

  • Nat Commun. 2019 Jun 13;10(1):2613. doi: 10.1038/s41467-019-10384-w.
Anja Greule 1 2,  Thierry Izoré 1 2,  Dumitrita Iftime 3,  Julien Tailhades 1 2,  Melanie Schoppet 1 2,  Yongwei Zhao 1 2,  Madeleine Peschke 4,  Iftekhar Ahmed 5,  Andreas Kulik 3,  Martina Adamek 3,  Robert J A Goode 1 6,  Ralf B Schittenhelm 1 6,  Joe A Kaczmarski 7,  Colin J Jackson 7,  Nadine Ziemert 3,  Elizabeth H Krenske 5,  James J De Voss 5,  Evi Stegmann 8 9,  Max J Cryle 10 11
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, The Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
  • 2 EMBL Australia, Monash University, Clayton, VIC, 3800, Australia.
  • 3 Interfaculty Institute of Microbiology and Infection Medicine Tübingen, Microbiology/Biotechnology, University of Tübingen, Auf der Morgenstelle 28, 72076, Tübingen, Germany.
  • 4 Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120, Heidelberg, Germany.
  • 5 Department of Chemistry, The University of Queensland, St Lucia, QLD, 4072, Australia.
  • 6 Monash Biomedical Proteomics Facility, Monash University, Clayton, VIC, 3800, Australia.
  • 7 Research School of Chemistry, The Australian National University, Acton, ACT, 2601, Australia.
  • 8 Interfaculty Institute of Microbiology and Infection Medicine Tübingen, Microbiology/Biotechnology, University of Tübingen, Auf der Morgenstelle 28, 72076, Tübingen, Germany. evi.stegmann@biotech.uni-tuebingen.de.
  • 9 German Centre for Infection Research (DZIF), Partner Site Tübingen, 72076, Tübingen, Germany. evi.stegmann@biotech.uni-tuebingen.de.
  • 10 Department of Biochemistry and Molecular Biology, The Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. max.cryle@monash.edu.
  • 11 EMBL Australia, Monash University, Clayton, VIC, 3800, Australia. max.cryle@monash.edu.
PMID: 31197182 DOI: 10.1038/s41467-019-10384-w
Abstract

Kistamicin is a divergent member of the Glycopeptide antibiotics, a structurally complex class of important, clinically relevant Antibiotics often used as the last resort against resistant bacteria. The extensively crosslinked structure of these Antibiotics that is essential for their activity makes their chemical synthesis highly challenging and limits their production to Bacterial fermentation. Kistamicin contains three crosslinks, including an unusual 15-membered A-O-B ring, despite the presence of only two Cytochrome P450 Oxy Enzymes thought to catalyse formation of such crosslinks within the biosynthetic gene cluster. In this study, we characterise the kistamicin cyclisation pathway, showing that the two Oxy Enzymes are responsible for these crosslinks within kistamicin and that they function through interactions with the X-domain, unique to Glycopeptide antibiotic biosynthesis. We also show that the kistamicin OxyC Enzyme is a promiscuous biocatalyst, able to install multiple crosslinks into Peptides containing phenolic Amino acids.

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