Researchers Develop a Platform to Produce Brand-new Antibiotics
Fruiting bodies from the mushroom Clitopilus passeckerianus generated in the laboratory. Credit: University of Bristol
Combining the innovations of synthetic biology with biology and chemistry, a team of scientists at the University of Bristol have generated a brand-new platform that will allow the production of desperately needed brand-new antibiotics.
With resistance growing to existing antibiotics, there is a vital and urgent need for the discovery and development of new antibiotics that are cost effective.
Promising developments are derivatives of the antibiotic pleuromutilin, with the core pleuromutilin isolated from the mushroom Clitopilus passeckerianus.
Pleuromutilin derivatives are potent antibacterial drugs but often require difficult chemical modifications.
In a new paper published in Nature Communications, the Bristol team report the genetic characterisation of the steps involved in pleuromutilin biosynthesis through heterologous expression and generate a semi-synthetic 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.
Professor Chris Willis, from the School of Chemistry, said: "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."
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, pleuromutilins 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).
Professor Gary Foster from the School of Biological Sciences who led the team, with Dr Andy Bailey, added: "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."
This article has been republished from materials provided by University of Bristol. Note: material may have been edited for length and content. For further information, please contact the cited source.
'Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates novel bioactive semi-synthetic derivatives' by F. Alberti, K. Khairudin, E. Rodriguez Venegas, J. Davies, Patrick. Hayes, C. Willis, A. Bailey and G. Foster in Nature Communications 10.1038/s41467-017-01659-1
Targeted Drug Could be Used to Treat Advanced Cancers Located Anywhere in the BodyNews
A new targeted drug could be used to treat a small number of advanced cancers no matter where they grow in the body.READ MORE
Human Malaria Parasites Grown for the First Time in Dormant FormNews
One of the biggest obstacles to eradicating malaria is a dormant form of the parasite which is resistant to most antimalarial drugs and can reawaken years later, causing disease relapse. Researchers have shown they can grow the dormant parasite in engineered human liver tissue for several weeks, allowing them to closely study how the parasite becomes dormant, what vulnerabilities it may have, and how it springs back to life.READ MORE
Bacteria Produce More Substances Than Genetics PredictedNews
Tandem mass spectrometry has revealed that Streptomyces chartreusis, an antibiotic-producing bacterium, releases more metabolites into the surrounding medium than scientists assumed based on the analysis of the genome. They might include molecules that are of interest as potential pharmaceutical agents.READ MORE