Inhibition of Escherichia coli glycosyltransferase MurG and Mycobacterium tuberculosis Gal transferase by uridine-linked transition state mimics.
Glycosyltransferase MurG catalyses the transfer of N-acetyl-d-glucosamine to lipid intermediate I on the bacterial peptidoglycan biosynthesis pathway, and is a target for development of new antibacterial agents. A transition state mimic was designed for MurG, containing a functionalised proline, linked through the alpha-carboxylic acid, via a spacer, to a uridine nucleoside. A set of 15 functionalised prolines were synthesised, using a convergent dipolar cycloaddition reaction, which were coupled via either a glycine, proline, sarcosine, or diester linkage to the 5'-position of uridine. The library of 18 final compounds were tested as inhibitors of Escherichia coli glycosyltransferase MurG. Ten compounds showed inhibition of MurG at 1mM concentration, the most active with IC(50) 400microM. The library was also tested against Mycobacterium tuberculosis galactosyltransferase GlfT2, and one compound showed effective inhibition at 1mM concentration.
Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom.
Amy E
AE
Trunkfield
Sudagar S
SS
Gurcha
Gurdyal S
GS
Besra
Timothy D H
TD
Bugg
D001419:Bacteria / Q000187:drug effects; D002236:Carbohydrate Conformation; D002473:Cell Wall / Q000187:drug effects / Q000201:enzymology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D005998:Glycine / Q000737:chemistry; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006860:Hydrogen Bonding; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D018716:Molecular Mimicry; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D011392:Proline / Q000737:chemistry; D011487:Protein Conformation; D012521:Sarcosine / Q000737:chemistry; D014529:Uridine / Q000737:chemistry*
D011392:Proline; D016695:Glycosyltransferases; D005700:Galactosyltransferases; D005998:Glycine; D014529:Uridine; D012521:Sarcosine