Structure of Staphylococcus aureus ClpP Bound to the Covalent Active-Site Inhibitor Cystargolide A.

Autor:	Illigmann A; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Auf der Morgenstelle 28, 72076, Tübingen, Germany., Vielberg MT; Chair of Biochemistry, Centre for Protein Assemblies, Technical University Munich, Ernst-Otto-Fischer-Strasse 8, 85748, Garching, Germany., Lakemeyer M; Chair of Organic Chemistry II, Technical University Munich, School of Natural Sciences, Center for Functional Protein Assemblies (CPA), Ernst-Otto-Fischer-Straße 8/I, 85748, Garching b.München, Germany.; Current address: Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 10, 07743, Jena, Germany., Wolf F; Synthetic Biology of Anti-infective Agents, Pharmaceutical Institute, University of Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany., Dema T; Institute of Organic Chemistry, University of Tübingen, Auf der Morgenstelle 18, 72076, Tübingen, Germany., Stange P; Institute of Organic Chemistry, University of Tübingen, Auf der Morgenstelle 18, 72076, Tübingen, Germany., Kuttenlochner W; Chair of Biochemistry, Centre for Protein Assemblies, Technical University Munich, Ernst-Otto-Fischer-Strasse 8, 85748, Garching, Germany., Liebhart E; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Auf der Morgenstelle 28, 72076, Tübingen, Germany., Kulik A; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Auf der Morgenstelle 28, 72076, Tübingen, Germany., Staudt ND; Synthetic Biology of Anti-infective Agents, Pharmaceutical Institute, University of Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany., Malik I; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Auf der Morgenstelle 28, 72076, Tübingen, Germany., Grond S; Institute of Organic Chemistry, University of Tübingen, Auf der Morgenstelle 18, 72076, Tübingen, Germany., Sieber SA; Chair of Organic Chemistry II, Technical University Munich, School of Natural Sciences, Center for Functional Protein Assemblies (CPA), Ernst-Otto-Fischer-Straße 8/I, 85748, Garching b.München, Germany., Kaysser L; Synthetic Biology of Anti-infective Agents, Pharmaceutical Institute, University of Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.; Pharmazeutische Biologie, Institut für Wirkstoffentwicklung, Universitätsklinikum Leipzig, Eilenburger Strasse 15a, 04317, Leipzig, Germany., Groll M; Chair of Biochemistry, Centre for Protein Assemblies, Technical University Munich, Ernst-Otto-Fischer-Strasse 8, 85748, Garching, Germany., Brötz-Oesterhelt H; Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Auf der Morgenstelle 28, 72076, Tübingen, Germany.; Cluster of Excellence Controlling Microbes to Fight Infections, University of Tübingen, Auf der Morgenstelle 28, 72076, Tübingen, Germany.
Jazyk:	angličtina
Zdroj:	Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Jan 15; Vol. 63 (3), pp. e202314028. Date of Electronic Publication: 2023 Dec 12.
DOI:	10.1002/anie.202314028
Abstrakt:	The caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Herein, we describe the potent cystargolides as the first natural β-lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic gene cluster in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target. We show the inhibition of Staphylococcus aureus ClpP by cystargolide A and B by different biochemical methods in vitro. Synthesis of semisynthetic derivatives and probes with improved cell penetration allowed us to confirm ClpP as a specific target in S. aureus cells and to demonstrate the anti-virulence activity of this natural product class. Crystal structures show cystargolide A covalently bound to all 14 active sites of ClpP from S. aureus, Aquifex aeolicus, and Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by β-lactones, the predominant class of ClpP inhibitors. (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze:	MEDLINE
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