Miller, Gavin

School of Chemical and Physical Sciences Manchester (UK)

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


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


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.

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