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

Fabrizio Alberti, Khairunisa Khairudin, Edith Rodriguez Venegas, Jonathan A. Davies, Patrick M. Hayes, Christine L. Willis, Andy M. Bailey () and Gary D. Foster ()
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Fabrizio Alberti: University of Bristol
Khairunisa Khairudin: University of Bristol
Edith Rodriguez Venegas: University of Bristol
Jonathan A. Davies: University of Bristol
Patrick M. Hayes: University of Bristol
Christine L. Willis: University of Bristol
Andy M. Bailey: University of Bristol
Gary D. Foster: University of Bristol

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01659-1

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