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

preprint
submitted on 26.05.2020 and posted on 27.05.2020 by Laura Beswick, Eleni Dimitriou, Sanaz Ahmadipour, Ayesha Zafar, Martin Rejzek, Johannes Reynisson, Robert Field, Gavin Miller

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.

Funding

Engineering and Physical Sciences Research Council, EP/P000762/1

Biological Science Research Council, BBS/E/J/000PR9790

InnovateUK,BB/M02903411 and EP/N033167/10

History

Email Address of Submitting Author

g.j.miller@keele.ac.uk

Institution

Keele University

Country

United Kingdom

ORCID For Submitting Author

0000-0001-6533-3306

Declaration of Conflict of Interest

No conflict of interest

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