Bioengineering of next generation lipoglycopeptide antibiotics

Bioengineering of next generation lipoglycopeptide antibiotics

Funded Value: £690,996
Funded Period: Oct 13 – Sep 17
Funder: BBSRC
Principal Investigator: Jason Micklefield
Research Topic: biochemistry & physiology, biological & medicinal chem.; catalysis & enzymology; chemical biology

One of the major challenges in healthcare is the provision of new antimicrobial agents that can combat antibiotic-resistant pathogens (superbugs), which are widely recognised as a major global threat. It is essential that new approaches are developed that can deliver the next generation of antibiotics, which are urgently required to combat emerging drug-resistant pathogens. This project aims to develop novel biosynthetic engineering methodologies to generate structurally diverse variants of the enduracidin and ramoplanin family of lipoglycopeptide antibiotics, which have entered phase III clinical trials. Despite their high potency and significant clinical potential, the lipoglycopeptide antibiotics are highly structurally complex natural products. Consequently traditional semisynthesis and total synthesis approaches are unlikely to deliver more effective variants. To this end, we will explore the biosynthesis of the lipoglycopeptides, characterising the key enzymes involved in lipoglycopeptide assembly. The new biosynthetic insights will be used to guide the development of bioengineering strategies aimed at altering the glycosylation, halogenation and lipidation patterns, as well as the amino acid sequence of the lipoglycopeptides. The long-term objective is to produce more effective next generation lipoglycopeptide antibiotics, for subsequent development with industrial partners.

The bioengineering methodologies that we develop will be generic and can also be used to engineer a wide range of derivatives for other promising classes of antibiotics (e.g. vancomycins and mannopeptimycins), as well as other natural product variants for alternative therapeutic and agrochemical applications. This project also addresses key environmental issues, by providing methods that can lead to the more environmentally benign and sustainable biomanufacture of pharmaceuticals, agrochemicals, and other products from renewable resources, via fermentation.

This collaboration with GSK will involve interactions with the Synthetic Biochemistry team (Stevenage), who aim to develop environmentally sustainable and economically viable processes for producing therapeutic lead compounds and intermediates. We will also collaborate with the Biotechnology & Environmental Shared Services (BESS) group, within GSK manufacturing (Worthing). BESS are involved in the discovery and manufacture of pharmaceutically relevant fermentation products, using a variety of microorganisms including Streptomyces. GSK have begun to use genome sequencing to guide metabolic engineering in Streptomyces, and they will benefit from collaboration through our development of a generic set of methodologies, including genome mining, strain optimisation and pathway engineering, that could be applied within their own research and manufacturing programmes.

“This project addresses key environmental issues, by providing methods that can lead to the more environmentally benign and sustainable biomanufacture of pharmaceuticals, agrochemicals, and other products from renewable resources, via fermentation.”

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