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

Journal of the American Chemical Society
Helen R JosephineRex F Pratt

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.

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Citations

May 5, 2010·Nature Reviews. Microbiology·Michael A KohanskiJames J Collins
Aug 18, 2012·Molecular BioSystems·Haihong HaoZonghui Yuan
Oct 4, 2005·Protein Science : a Publication of the Protein Society·Noureddine RhaziJean-Marie Frère
Feb 23, 2012·Organic & Biomolecular Chemistry·Sylvain AubryDavid Crich
Nov 9, 2016·Antimicrobial Agents and Chemotherapy·Wei ChenChristopher Davies
Apr 24, 2020·Journal of Computational Chemistry·Qianyi Cheng, Nathan J DeYonker
Aug 1, 2019·The Journal of Biological Chemistry·Avinash SinghChristopher Davies
May 8, 2014·Journal of Chemical Theory and Computation·Jacqueline C HargisH Lee Woodcock

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