Discovery, biosynthetic engineering, and chemical modification of bioactive natural products
We study natural products of bacteria and fungi with interesting chemical and biological properties, making use of techniques from microbiology, synthetic and analytical chemistry, and molecular biology. The broad aim is to discover new, interesting natural products, and to apply a range of chemical and biological strategies to generate unnatural variants of natural products.
Our main focus is on the azinomycins, bacterial natural products with DNA crosslinking and anticancer activity. They are of particular interest because they contain an aziridine ring, a very rare feature of natural products, which is responsible for their biological activity.
After early work on studying the biosynthetic pathway to the azinomycins and the biosynthetic gene cluster, we are now concentrating on the generation of unnatural azinomycin analogues, with the goal of improving cell selectivity and reducing toxicity by conjugation to tumour targeting agents. We synthesise unnatural analogues of the naphthoic acid fragment and feed them to the azinomycin producing organism, where they are biotransformed into azinomycin analogues. We are also exploring selective chemical reactions to modify the azinomycins, without affecting the aziridine and epoxide groups which are essential for the biological activity.
We are also working on the discovery of new natural products from bacteria and fungi. We are particularly focussed on natural products which share part of the azinomycin biosynthetic pathway, but we work with Dr. Sanjib Bhakta's mycobacteria research laboratory to assess their antibiotic activity.
