Next generation Glucose-1-phosphate thymidylyltransferase (RmlA) inhibitors: An extended SAR study to direct future design.

Autor: Xiao G; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Alphey MS; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Tran F; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Pirrie L; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Milbeo P; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Zhou Y; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Bickel JK; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Kempf O; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Kempf K; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK., Naismith JH; Division of Structural Biology, University of Oxford, and The Rosalind Franklin Institute, Harwell Campus, OX11 0FA, UK. Electronic address: james.naismith@strubi.ox.ac.uk., Westwood NJ; School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, St Andrews Fife KY16 9ST, UK. Electronic address: njw3@st-andrews.ac.uk.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 Nov 15; Vol. 50, pp. 116477. Date of Electronic Publication: 2021 Oct 16.
DOI: 10.1016/j.bmc.2021.116477
Abstrakt: The monosaccharide l-Rhamnose is an important component of bacterial cell walls. The first step in the l-rhamnose biosynthetic pathway is catalysed by glucose-1-phosphate thymidylyltransferase (RmlA), which condenses glucose-1-phosphate (Glu-1-P) with deoxythymidine triphosphate (dTTP) to yield dTDP-d-glucose. In addition to the active site where catalysis of this reaction occurs, RmlA has an allosteric site that is important for its function. Building on previous reports, SAR studies have explored further the allosteric site, leading to the identification of very potent P. aeruginosa RmlA inhibitors. Modification at the C6-NH 2 of the inhibitor's pyrimidinedione core structure was tolerated. X-ray crystallographic analysis of the complexes of P. aeruginosa RmlA with the novel analogues revealed that C6-aminoalkyl substituents can be used to position a modifiable amine just outside the allosteric pocket. This opens up the possibility of linking a siderophore to this class of inhibitor with the goal of enhancing bacterial cell wall permeability.
(Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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