Exploiting microbial genomics and synthetic biology for discovery and optimisation of novel natural product therapeutics

Microorganisms produce a wealth of structurally diverse natural products with potent biological activities, such as antibiotics, insecticides, fungicides, immunosuppressants and anticancer agents. Microbial natural products and their (semi-) synthetic derivatives therefore have important applications in medicine and agriculture. The continuing rise in resistance to antibiotics and cancer chemotherapeutics remains one of the major concerns for healthcare institutions worldwide and novel drugs are therefore urgently needed. Given the enormous success of microbial metabolites as starting points for the development of such products, there is a continuous interest in finding new biologically active natural products as a source of novel drug leads. This project will therefore use a genome mining approach to discover novel and unusual natural product biosynthetic gene clusters from underexplored Gram-negative bacteria. The metabolic products of these gene clusters will be identified and their biological function and mode of action will be examined. Biosynthetic pathways of interest will be investigated and the catalytic mechanisms of enzymes responsible for highly unusual transformations will be elucidated. This knowledge will then be exploited for biosynthetic pathway engineering, aimed at further optimising the natural products for pharmaceutical or agrochemical applications.