Targeted Chemoenzymatic Synthesis of Sugar Nucleotide Probes Reveal an Inhibitor of the GDP-D-Mannose Dehydrogenase from Pseudomonas Aeruginosa

Sufferers of the autosomal recessive genetic disorder cystic fibrosis are at extremely high risk for contracting chronic lung infections. Over their lifetime one bacterial strain in particular, Pseudomonas aeruginosa, becomes the dominant pathogen. Bacterial strains incur loss-of-function mutations in the mucA gene that lead to a phenomenon known as mucoid conversion, resulting in copious secretion of alginate, a carbohydrate exopolysaccharide. Strategies that can stop the production of alginate in mucoid Pseudomonas aeruginosa infections are therefore of paramount importance. To aid in this we developed a series of sugar nucleotide chemical tools to probe an enzyme critical to alginate biosynthesis, guanosine diphosphate mannose dehydrogenase (GMD). This enzyme catalyses the irreversible formation of the alginate sugar nucleotide building block, guanosine diphosphate mannuronic acid. Using a chemoenzymatic strategy we accessed a series of modified sugar nucleotides, identifying a C6-amide derivative of the native substrate as a micromolar inhibitor of GMD. This discovery will provide a framework for wider inhibition strategies against GMD to be developed.