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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
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 | |||||||||||||||
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| 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: |
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| 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: |
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