Biosynthesis of pleuromutilin congeners using an Aspergillus oryzae expression platform

Fabrizio Alberti, Khairunisa Khairudin, Jonathan Davies, Suphattra Sangmalee, Chris L Willis, Gary D Foster, Andrew M. Bailey

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

3 Citations (Scopus)

Abstract

Pleuromutilin is an antibiotic diterpenoid made by Clitopilus passeckerianus and related fungi, and it is the
progenitor of a growing class of semi-synthetic antibiotics used in veterinary and human medicine. To
harness the biotechnological potential of this natural product class, a full understanding of its
biosynthetic pathway is essential. Previously, a linear pathway for pleuromutilin biosynthesis was
established. Here we report two shunt pathways involving Pl-sdr and Pl-atf that were identified through
the rational heterologous expression of combinations of pleuromutilin biosynthetic genes in Aspergillus
oryzae. Three novel pleuromutilin congeners were isolated, and their antimicrobial activity was
investigated, alongside that of an additional derivative produced through a semi-synthetic approach. It
was observed that the absence of various functional groups – 3 ketone, 11 hydroxyl group or 21 ketone
– from the pleuromutilin framework affected the antibacterial activity of pleuromutilin congeners. This
study expands our knowledge on the biosynthesis of pleuromutilin and provides avenues for the
development of novel pleuromutilin analogues by combining synthetic biology and synthetic chemistry.
Original languageEnglish
Pages (from-to)3826-3833
Number of pages8
JournalChemical Science
Volume14
Issue number14
DOIs
Publication statusPublished - 15 Mar 2023

Bibliographical note

Funding Information:
Dr Colin Lazarus is thanked for providing expression vectors for the transformation of A. oryzae; the NMR spectroscopy and MS facilities and teams of the University of Bristol are thanked for data collection and helpful discussion. KK was supported by a scholarship from Majlis Amanah Rakyat. JAD was supported by a scholarship from the EPSRC, Bristol Chemical Sciences Centre for Doctoral Training (EP/L015366/1). FA would like to acknowledge current funding from UKRI through a Future Leaders Fellowship (MR/V022334/1).

Publisher Copyright:
© 2023 The Royal Society of Chemistry.

Structured keywords

  • BCS and TECS CDTs

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