The perfect penicillin? Inhibition of a bacterial DD-peptidase by peptidoglycan-mimetic beta-lactams.
6-(Glycyl-l-alpha-aminopimelyl)-aminopenicillanic acid and 7-(glycyl-l-alpha-aminopimelyl)-aminocephalosporanic acid have been synthesized as Streptomyces sp. peptidoglycan-mimetic beta-lactams. These compounds inactivate the Streptomyces R61 DD-peptidase with rate constants of 1.5 x 107 s-1 M-1 and 5.6 x 105 s-1 M-1, respectively. The former compound is thus the most effective beta-lactam inhibitor of a DD-peptidase yet described. The analogous d-alanyl-d-alanine peptide has previously been shown to react with this enzyme with comparable efficiency, kcat/Km = 8.7 x 106 s-1 M-1. These results show that, in this case at least, incorporation of a peptidoglycan-mimetic side chain into a beta-lactam greatly enhances its activity as a DD-peptidase inhibitor. This result has interesting implications for beta-lactam design.
Josephine
Helen R
HR
Department of Chemistry, Wesleyan University, Lawn Avenue, Middletown, CT 06459, USA.
Kumar
Ish
I
Pratt
R F
RF
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010406:Penicillins / Q000737:chemistry* / Q000494:pharmacology; D010457:Peptidoglycan / Q000096:biosynthesis*; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; D013302:Streptomyces / Q000187:drug effects* / Q000201:enzymology; D013379:Substrate Specificity
D000900:Anti-Bacterial Agents; D010406:Penicillins; D010457:Peptidoglycan; D002268:Carboxypeptidases; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase