Molecular Mechanisms of Gladiolin Biosynthesis

Lead Research Organisation: University of Warwick
Department Name: Warwick Medical School


Programme overview:
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.

The World Health Organisation describes antimicrobial resistance (AMR) as one of the greatest threats to global health. AMR currently causes tens of thousands of deaths per year worldwide, predicted to rise to ten million per year by 2050, costing the global economy $100 trillion. New antibiotics are desperately needed to combat this escalating crisis. Natural product molecules from living organisms such as bacteria and fungi, often possess antimicrobial activity and could be a source of new pharmaceuticals. Gladiolin, isolated from the bacterium Burkholderia gladioli BCC0238, possesses activity against Mycobacterium tuberculosis (TB).

Gladiolin is biosynthesised by a polyketide synthase (PKS) multienzyme formed of repeated functional units which are used in a specific order to produce the final product. Modular PKSs are composed of independently folded catalytic domains that incorporate and assemble a polyketide (PK) thioester via a series of covalently bound intermediates. By elucidation of the protein-protein interactions which facilitate transfer and modification of the growing PK chain, and the activity and substrate specificity of these proteins, it may be possible to produce genetically engineered hybrid PKSs.

This project aims to increase our understanding of the PKS responsible for the biosynthesis of gladiolin, with a view to production of novel PK analogues with higher activity more applicable for use as pharmaceuticals.


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