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

Anja Greule, Thierry Izoré, Dumitrita Iftime, Julien Tailhades, Melanie Schoppet, Yongwei Zhao, Madeleine Peschke, Iftekhar Ahmed, Andreas Kulik, Martina Adamek, Robert J. A. Goode, Ralf B. Schittenhelm, Joe A. Kaczmarski, Colin J. Jackson, Nadine Ziemert, Elizabeth H. Krenske, James J. Voss, Evi Stegmann () and Max J. Cryle ()
Additional contact information
Anja Greule: The Monash Biomedicine Discovery Institute, Monash University
Thierry Izoré: The Monash Biomedicine Discovery Institute, Monash University
Dumitrita Iftime: University of Tübingen
Julien Tailhades: The Monash Biomedicine Discovery Institute, Monash University
Melanie Schoppet: The Monash Biomedicine Discovery Institute, Monash University
Yongwei Zhao: The Monash Biomedicine Discovery Institute, Monash University
Madeleine Peschke: Max Planck Institute for Medical Research
Iftekhar Ahmed: The University of Queensland
Andreas Kulik: University of Tübingen
Martina Adamek: University of Tübingen
Robert J. A. Goode: The Monash Biomedicine Discovery Institute, Monash University
Ralf B. Schittenhelm: The Monash Biomedicine Discovery Institute, Monash University
Joe A. Kaczmarski: The Australian National University
Colin J. Jackson: The Australian National University
Nadine Ziemert: University of Tübingen
Elizabeth H. Krenske: The University of Queensland
James J. Voss: The University of Queensland
Evi Stegmann: University of Tübingen
Max J. Cryle: The Monash Biomedicine Discovery Institute, Monash University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10384-w

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