Novel Antibiotic Production Platform Harnesses Synthetic Biology and Chemistry

Researchers from the University of Bristol say they have combined synthetic biology and chemistry to create a modern technology platform to allow the production of novel antibiotics to combat increasing microbial drug resistance.

The team is working on derivatives of pleuromutilin, with the core pleuromutilin isolated from the mushroom Clitopilus passeckerianus. Pleuromutilin derivatives are potent antibacterial drugs but often require difficult chemical modifications, according to the scientists.

In a new paper (“Heterologous Expression Reveals the Biosynthesis of the Antibiotic Pleuromutilin and Generates Bioactive Semi-Synthetic Derivatives”), published in Nature Communications, the Bristol researchers report the genetic characterization of the steps involved in pleuromutilin biosynthesis through heterologous expression and generate a semisynthetic pleuromutilin derivative with enhanced antibiotic activity.  This was achieved by taking the complete genetic pathway for pleuromutilin production, containing seven genes, from the mushroom and rebuilding it in the industrially useful filamentous fungus Aspergillus oryzae, traditionally used to make soy sauce. This then generated a unique platform of Aspergillus lines with combinations of the pathway genes to allow new compounds to be synthesized.

“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 characterization 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,” write the investigators.

“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.”

“This is a classic case where nature has produced something really useful, but combining nature with chemistry through a synthetic biology approach we are able to make things even better,” says Christine Willis, Ph.D., from the School of Chemistry, adding that these new compounds are some of the only new class of antibiotics to join the market recently as human therapeutics.

Furthermore, with their novel mode of action and lack of cross-resistance, pleuromutilin’s and their derivatives represent a class with further great potential, particularly for treating resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and extensively drug-resistant tuberculosis (XTB), according to Dr. Willis.

Gary Foster, Ph.D., from the School of Biological Sciences who led the team, and Andy Bailey, Ph.D., add that “This research is very exciting as it also paves the way for future characterization of biosynthetic pathways of other basidiomycete natural products in ascomycete heterologous hosts. Many mushrooms have never even been examined and act as an untapped resource. The platform also opens up new possibilities of further chemical modification for the growing class of potent antibiotics.”

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