Ronak Tilvawala, Michael Cammarata, S.Synthesis and Kinetic Analysis of Two Conformationally Restricted Peptide Substrates of Escherichia coli Penicillin-Binding Protein 5. Kinetic Evidence for a Second Ligand Binding Site on Streptococcus pneumoniae Penicillin-Binding Protein 2x. Journal of the American Chemical Society 2020, 142 Substrate and Stereochemical Control of Peptidoglycan Cross-Linking by Transpeptidation by Escherichia coli PBP1B. β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium. This article is cited by 33 publications.
That this question needs to be asked casts fascinating shadows on current studies of penicillin-binding proteins for new drug design. Why do the majority of penicillin-binding proteins not recognize elements of local peptidoglycan structure? Possible answers are discussed. The former result is unexpected and interesting. Such peptides and β-lactams do react at greatly enhanced rates with certain soluble low molecular weight enzymes (R61 and R39 dd-peptidases). Neither peptides nor β-lactams with appropriate peptidoglycan-mimetic side chains react with the solubilized constructs of membrane-bound penicillin binding proteins (the first five enzymes above) at rates exceeding those of generic analogues. The results of these experiments mirror and expand the previous results with peptides. The theme of these experiments is expanded in the present paper where we describe the synthesis of a series of β-lactams (penicillins and cephalosporins) containing peptidoglycan-mimetic side chains and the kinetics of their inhibition of a panel of penicillin-binding proteins spanning the major classes ( Escherichia coli PBP 2 and PBP 5, Streptococcus pneumoniae PBP 1b, PBP 2x and PBP 3, the Actinomadura R39 dd-peptidase, and the Streptomyces R61 dd-peptidase). We have previously shown that representatives of the former group are ineffective at catalyzing the hydrolysis/aminolysis of peptidoglycan-mimetic peptides in vitro. The latter group consists of dd-carboxypeptidases, and their inhibition by β-lactams is generally not fatal to bacteria. Members of the former group act as transpeptidases in vivo, and their inhibition by β-lactams leads to cessation of bacterial growth. They have been classified into two major groups, one of high molecular weight, the other of low.
Bacteria, in general, carry several such enzymes localized on the outside of their cell membrane to catalyze the final step in cell wall (peptidoglycan) synthesis. Β-Lactams exert their antibiotic action through their inhibition of bacterial dd-peptidases (penicillin-binding proteins).
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