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Beswick, Laura, Dimitriou, Eleni, Ahmadipour, Sanaz, Zafar, Ayesha, Rejzek, Martin, Reynisson, Jóhannes, Field, Robert A. 
ORCID: https://orcid.org/0000-0001-8574-0275 and Miller, Gavin J.
(2020)
Inhibition of the GDP- d -Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes.
ACS Chemical Biology, 15 (12).
pp. 3086-3092.
ISSN 1554-8929
Abstract
Sufferers of 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 mucoid conversion, resulting in copious secretion of the exopolysaccharide alginate. Strategies that stop the production of alginate in mucoid Pseudomonas aeruginosa infections are therefore of paramount importance. To aid in this, a series of sugar nucleotide tools to probe an enzyme critical to alginate biosynthesis, guanosine diphosphate mannose dehydrogenase (GMD), have been developed. GMD catalyzes the irreversible formation of the alginate building block, guanosine diphosphate mannuronic acid. Using a chemoenzymatic strategy, we accessed a series of modified sugar nucleotides, identifying a C6-amide derivative of guanosine diphosphate mannose as a micromolar inhibitor of GMD. This discovery provides a framework for wider inhibition strategies against GMD to be developed.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding Information: The Engineering and Physical Research Council (EPSRC) are thanked for project grant funding (No. EP/P000762/1) to G.J.M. at Keele. Work at the MIB/JIC is supported by the Biotechnology and Biological Science Research Council (BBSRC) Institute Strategic Program on Molecules from Nature to Products and Pathways (No. BBS/E/J/000PR9790) and the InnovateUK IBCatalyst (Nos. BB/M02903411 and EP/N033167/10). We also thank the EPSRC UK National Mass Spectrometry Facility (NMSF) at Swansea University, P. Tipton (University of Missouri) for providing the GMD plasmid, and T. Lowary (University of Alberta) for providing the GDP-mannose pyrophosphorylase clone. Publisher Copyright: © 2020 American Chemical Society. |
| Uncontrolled Keywords: | biochemistry,molecular medicine ,/dk/atira/pure/subjectarea/asjc/1300/1303 |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 02 Sep 2024 13:31 |
| Last Modified: | 25 Sep 2024 18:05 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/96426 |
| DOI: | 10.1021/acschembio.0c00426 |
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