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Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives

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Alberti, Fabrizio, Khairudin, Khairunisa, Venegas, Edith Rodriguez, Davies, Jonathan A., Hayes, Patrick M., Willis, Christine L., Bailey, Andy M. and Foster, Gary D. (2017) Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives. Nature Communications, 8 (1). 1831. doi:10.1038/s41467-017-01659-1 ISSN 2041-1723.

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Official URL: http://dx.doi.org/10.1038/s41467-017-01659-1

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Abstract

The rise in antibiotic resistance is a major threat for human health. Basidiomycete fungi represent an untapped source of underexploited antimicrobials, with pleuromutilin—a diterpene produced by Clitopilus passeckerianus—being the only antibiotic from these fungi leading to commercial derivatives. Here we report genetic characterisation of the steps involved in pleuromutilin biosynthesis, through rational heterologous expression in Aspergillus oryzae coupled with isolation and detailed structural elucidation of the pathway intermediates by spectroscopic methods and comparison with synthetic standards. A. oryzae was further established as a platform for bio-conversion of chemically modified analogues of pleuromutilin intermediates, and was employed to generate a semi-synthetic pleuromutilin derivative with enhanced antibiotic activity. These studies pave the way for future characterisation of biosynthetic pathways of other basidiomycete natural products in ascomycete heterologous hosts, and open up new possibilities of further chemical modification for the growing class of potent pleuromutilin antibiotics.

Item Type: Journal Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Antibiotics, Anti-infective agents -- Synthesis, Basidiomycetes, Drug resistance in microorganisms
Journal or Publication Title: Nature Communications
Publisher: Nature Publishing Group
ISSN: 2041-1723
Official Date: 28 November 2017
Dates:
DateEvent
28 November 2017Available
6 October 2017Accepted
Volume: 8
Number: 1
Article Number: 1831
DOI: 10.1038/s41467-017-01659-1
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 29 November 2017
Date of first compliant Open Access: 29 November 2017
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
UNSPECIFIEDUniversity of Bristolhttp://dx.doi.org/10.13039/501100000883
UNSPECIFIEDConsejo Nacional de Ciencia y Tecnologíahttp://dx.doi.org/10.13039/501100007350
EP/L015366/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
BB/L01386X/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
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