title: An Aromatic Hydroxyamide Attenuates Multiresistant Staphylococcus aureus Toxin Expression.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) causes severe infections with only few effective antibiotic therapies currently available. To approach this challenge, chemical entities with a novel and resistance-free mode of action are desperately needed. Here, we introduce a new hydroxyamide compound that effectively reduces the expression of devastating toxins in various S. aureus and MRSA strains. The molecular mechanism was investigated by transcriptome analysis as well as by affinity-based protein profiling. Down-regulation of several pathogenesis associated genes suggested the inhibition of a central virulence-related pathway. Mass spectrometry-based chemical proteomics revealed putative molecular targets. Systemic treatment with the hydroxyamide showed significant reduction of abscess sizes in a MRSA mouse skin infection model. The absence of resistance development in vitro further underlines the finding that targeting virulence could lead to prolonged therapeutic options in comparison to antibiotics that directly address bacterial survival.
authors.affiliation: Department of Chemistry, AVIRU, GO-Bio-project of the Federal Ministry of Education and Research, FKZ: 031A131, Technische Universität München (TUM), Lichtenbergstrasse 4, 85747, Garching, Germany.
authors.forename: Jan
authors.identifier: http://orcid.org/0000-0003-3524-9060
authors.initials: J
authors.lastname: Vomacka
authors.affiliation: Department of Chemistry, AVIRU, GO-Bio-project of the Federal Ministry of Education and Research, FKZ: 031A131, Technische Universität München (TUM), Lichtenbergstrasse 4, 85747, Garching, Germany.
authors.forename: Vadim S
authors.initials: VS
authors.lastname: Korotkov
authors.affiliation: Department of Chemistry, AVIRU, GO-Bio-project of the Federal Ministry of Education and Research, FKZ: 031A131, Technische Universität München (TUM), Lichtenbergstrasse 4, 85747, Garching, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Bauer
authors.affiliation: Department of Chemistry, AVIRU, GO-Bio-project of the Federal Ministry of Education and Research, FKZ: 031A131, Technische Universität München (TUM), Lichtenbergstrasse 4, 85747, Garching, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Weinandy
authors.affiliation: Department of Chemistry, Chair of Organic Chemistry II, Center for Integrated Protein Science (CIPSM), Institute of Advanced Studies (IAS), Technische Universität München (TUM), Lichtenbergstrasse 4, 85747, Garching, Germany.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Kunzmann
authors.affiliation: Department of Chemistry, Chair of Organic Chemistry II, Center for Integrated Protein Science (CIPSM), Institute of Advanced Studies (IAS), Technische Universität München (TUM), Lichtenbergstrasse 4, 85747, Garching, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Krysiak
authors.affiliation: Department of Chemistry, Center for Integrated Protein Science (CIPSM), Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, 81377, Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Baron
authors.affiliation: Department of Chemistry, Universität Konstanz, Universitätsstrasse 10, 78457, Konstanz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Böttcher
authors.affiliation: Department of Chemistry, AVIRU, GO-Bio-project of the Federal Ministry of Education and Research, FKZ: 031A131, Technische Universität München (TUM), Lichtenbergstrasse 4, 85747, Garching, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Lorenz-Baath
authors.affiliation: Department of Chemistry, Chair of Organic Chemistry II, Center for Integrated Protein Science (CIPSM), Institute of Advanced Studies (IAS), Technische Universität München (TUM), Lichtenbergstrasse 4, 85747, Garching, Germany. stephan.sieber@tum.de.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000737:chemistry* / Q000187:drug effects* / Q000472:pathogenicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006877:Hydroxamic Acids
keywords: click chemistry; drug discovery; medicinal chemistry; proteomics; toxicology