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

Fabrizio Alberti, Khairunisa Khairudin, Edith Rodriguez Venegas, Jonathan Davies, Patrick Hayes, Chris Willis, Andrew M. Bailey*, Gary Foster

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

25 Citations (Scopus)
233 Downloads (Pure)

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.
Original languageEnglish
Article number1831
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 28 Nov 2017

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute
  • BCS and TECS CDTs

Keywords

  • Synthetic Biology

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