Autoren:	Barthels, Fabian Meyr, Jessica Hammerschmidt, Stefan J. Marciniak, Tessa Räder, Hans-Joachim Ziebuhr, Wilma Engels, Bernd Schirmeister, Tanja
Titel:	2-sulfonylpyrimidines as privileged warheads for the development of S. aureus sortase A inhibitors
Online-Publikationsdatum:	2-Mär-2023
Erscheinungsdatum:	2021
Sprache des Dokuments:	Englisch
Zusammenfassung/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-Sachgruppe:	570 Biowissenschaften 570 Life sciences 610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 09 Chemie, Pharmazie u. Geowissensch.
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8873
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	Frontiers in molecular biosciences 8
Seitenzahl oder Artikelnummer:	804970
Verlag:	Frontiers
Verlagsort:	Lausanne
Erscheinungsdatum:	2021
ISSN:	2296-889X
DOI der Originalveröffentlichung:	10.3389/fmolb.2021.804970
Enthalten in den Sammlungen:	JGU-Publikationen