The perfect penicillin? Inhibition of a bacterial DD-peptidase by peptidoglycan-mimetic beta-lactams

J Am Chem Soc. 2004 Jul 7;126(26):8122-3. doi: 10.1021/ja048850s.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Carboxypeptidases / antagonists & inhibitors*
  • Molecular Structure
  • Penicillins / chemistry*
  • Penicillins / pharmacology
  • Peptidoglycan / biosynthesis*
  • Serine-Type D-Ala-D-Ala Carboxypeptidase
  • Streptomyces / drug effects*
  • Streptomyces / enzymology
  • Substrate Specificity

Substances

  • Anti-Bacterial Agents
  • Penicillins
  • Peptidoglycan
  • Carboxypeptidases
  • Serine-Type D-Ala-D-Ala Carboxypeptidase