Synthesis and activity of 5'-uridinyl dipeptide analogues mimicking the amino terminal peptide chain of nucleoside antibiotic mureidomycin A.
A series of 5'-uridinyl dipeptides were synthesised which mimic the amino terminal chain of nucleoside antibiotic mureido omycin A. Aminoacyl-beta-alanyl- and aminoacyl-N-methyl-beta-alanyl- dipeptides were attached either via an ester linkage to the 5'-hydroxyl of uridine, or via an amide linkage to 5'-amino-5'-deoxyuridine. The most active inhibitor of Escherichia coli phospho-MurNAc-pentapeptide translocase (MraY) was 5'-O-(L-Ala-N-methyl-beta-alanyl)-uridine (13l), which also showed 97% enzyme inhibition at 2.35 mM concentration, and showed antibacterial activity at 100 microg/mL concentration against Pseudomonas putida. Both the central N-methyl amide linkage and a 5' uridine ester linkage were required for highest biological activity. Enzyme inhibition was shown to be competitive with Mg(2+). It is proposed that the primary amino terminus of the inhibitor binds in place of the Mg(2+) cofactor at the MraY active site, positioned via a cis-N-methyl amide linkage.
Howard
Nigel I
NI
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
Bugg
Timothy D H
TD
D000577:Amides / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001665:Binding Sites; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D015636:Magnesium Chloride / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D009705:Nucleosides / Q000494:pharmacology*; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors; D011549:Pseudomonas / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives*
D000577:Amides; D000900:Anti-Bacterial Agents; D004151:Dipeptides; D009705:Nucleosides; D015636:Magnesium Chloride; C059803:mureidomycin A; D010458:Peptidyl Transferases; D014529:Uridine