Miller, Gavin

Gavin read Chemistry at UMIST and was awarded an MChem in Medicinal Chemistry.

Abstract:

Chemoenzymatic synthesis of sugar nucleotide chemical biology tools to explore the GDP-D-mannose dehydrogenase from Pseudomonas aeruginosa

Topic:

The opportunistic human pathogen Pseudomonas aeruginosa (PA) causes chronic bacterial infections in cystic fibrosis patients, contributing to a reduction in lung function and increased mortality rates. The lung environment induces a switch of P. aeruginosa to its mucoid phenotype, which is characterised by an overproduction of the exopolysaccharide alginate. Composed of β-D-mannuronic acid and its C5 epimer α-L-guluronic acid, alginate is a key component in the formation of a bacterial biofilm, which increases persistence of the bacteria in the airways and retards antimicrobial treatments. Inspection of the PA biosynthetic pathway reveals a key enzyme involved in alginate production, GDP-mannose dehydrogenase (GMD), which catalyses an NAD+-dependent oxidation of GDP-D-Man to GDP-D-ManA: the alginate feedstock monosaccharide. We have designed and synthesised a series of GDP-Man probes to interact with the GMD active site, providing mechanistic insight and identifying the first sugar nucleotide inhibitor of GMD.