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Authors: Barthels, Fabian
Meyr, Jessica
Hammerschmidt, Stefan J.
Marciniak, Tessa
Räder, Hans-Joachim
Ziebuhr, Wilma
Engels, Bernd
Schirmeister, Tanja
Title: 2-sulfonylpyrimidines as privileged warheads for the development of S. aureus sortase A inhibitors
Online publication date: 2-Mar-2023
Year of first publication: 2021
Language: english
Abstract: Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar KI values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the SNAr reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog.
DDC: 570 Biowissenschaften
570 Life sciences
610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: Frontiers in molecular biosciences
Pages or article number: 804970
Publisher: Frontiers
Publisher place: Lausanne
Issue date: 2021
ISSN: 2296-889X
Publisher DOI: 10.3389/fmolb.2021.804970
Appears in collections:JGU-Publikationen

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