Penicillins and cephalosporins are active site-directed acylating agents: evidence in support of the substrate analogue hypothesis

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
D J WaxmanJ L Strominger

Abstract

Penicillin and related beta-lactam antibiotics are known to exert their bactericidal effects by inhibiting the cross-linking step (transpeptidation) of bacterial cell wall biosynthesis. Evidence is presented in support of the hypothesis that this inhibition results from covalent modification of the active site of sensitive enzymes as a consequence of the structural similarity between penicillin and the acyl-D-alanyl-D-alanine terminus of nascent peptidoglycan strands. Several predictions of this proposal have been verified experimentally. Penicillin-sensitive enzymes are inactivated, with the formation of a covalent, stoichiometric penicilloyl-enzyme complex in vitro. Acylenzyme intermediates have been trapped with several of these enzymes by using cell wall-related substrates. Sequence analysis of the peptides derived from active site-labelled enzymes has established that both penicilloyl and an acyl moiety derived from substrate are covalently bound to the same site, as an ester of serine 36, as predicted by the substrate analogue hypothesis. Sequences near the active site serine are homologous to sequences found in four beta-lactamases, supporting the proposal that penicillin-sensitive D-alanine carboxypeptidases and penicil...Continue Reading

Citations

Mar 1, 1994·The British Veterinary Journal·P Sarasola, Q A McKellar
Jun 8, 2010·Journal of Medicinal Chemistry·Jed F Fisher, Shahriar Mobashery
May 5, 2010·Nature Reviews. Microbiology·Michael A KohanskiJames J Collins
Oct 12, 2000·Food Additives and Contaminants·F J Schenck, S L Friedman
Jun 1, 1982·Antimicrobial Agents and Chemotherapy·G KleppeJ L Strominger
May 28, 2016·Journal of Medicinal Chemistry·R F Pratt
Jun 5, 1998·The Pediatric Infectious Disease Journal·M H MacrisJ B Zabriskie
Jan 22, 2020·FEMS Microbiology Letters·Jessica R SalasVictoriya V Volkova
Mar 7, 2019·Nature Reviews. Microbiology·Karen Bush, Patricia A Bradford
Dec 30, 2020·Chemical Reviews·Jed F Fisher, Shahriar Mobashery
Dec 1, 1981·Journal of Bacteriology·D J WaxmanJ L Strominger
Jan 1, 1985·Pharmacology & Therapeutics·D J Tipper

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