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Updated: Aug 3, 2025
A Customizable Approach for the Enzymatic Production and Purification of Diterpenoid Natural Products
Published on: October 4, 2019
Biosynthesis of pleuromutilin congeners using an Aspergillus oryzae expression platform
Fabrizio Alberti1, Khairunisa Khairudin1, Jonathan A Davies2
1School of Biological Sciences, University of Bristol 24 Tyndall Avenue Bristol BS8 1TQ UK F.Alberti@warwick.ac.uk Andy.Bailey@bristol.ac.uk.
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.
Insights
Researchers discovered new pleuromutilin antibiotic pathways using synthetic biology. This expands knowledge of pleuromutilin biosynthesis and aids in developing novel antibiotic analogues.
Area of Science:
- Microbiology
- Natural Product Chemistry
- Synthetic Biology
Background:
- Pleuromutilin, a diterpenoid antibiotic from fungi, is crucial for veterinary and human medicine.
- Understanding pleuromutilin's biosynthetic pathway is key to unlocking its biotechnological potential.
- A linear pathway was previously established, but shunt pathways remained unexplored.
Purpose of the Study:
- To elucidate novel pleuromutilin biosynthetic pathways.
- To identify new pleuromutilin congeners and assess their antimicrobial activities.
- To explore structure-activity relationships for pleuromutilin analogues.
Main Methods:
- Rational heterologous expression of pleuromutilin biosynthetic genes in *Aspergillus oryzae*.
- Isolation and characterization of novel pleuromutilin congeners.
- Antimicrobial activity assays and semi-synthetic modification.
Main Results:
- Two shunt pathways, involving *Pl-sdr* and *Pl-atf*, were identified.
- Three novel pleuromutilin congeners were isolated and characterized.
- Functional group modifications (3 ketone, 11 hydroxyl, 21 ketone) impact antibacterial activity.
Conclusions:
- This study reveals previously unknown pleuromutilin biosynthetic pathways.
- Novel pleuromutilin congeners exhibit varying antimicrobial activities based on structural modifications.
- Combining synthetic biology and chemistry offers a promising approach for developing new pleuromutilin-based antibiotics.
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