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dc.contributor.authorBeisel, Chase L
dc.date.accessioned2020-03-02T13:12:53Z
dc.date.available2020-03-02T13:12:53Z
dc.date.issued2020-01-16
dc.identifier.citationMethods. 2020 Jan 16. pii: S1046-2023(20)30020-7. doi: 10.1016/j.ymeth.2020.01.004.en_US
dc.identifier.issn1095-9130
dc.identifier.pmid31954772
dc.identifier.doi10.1016/j.ymeth.2020.01.004
dc.identifier.urihttp://hdl.handle.net/10033/622184
dc.description.abstractNew drugs are desperately needed to combat methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we report screening commercial kinase inhibitors for antibacterial activity and found the anticancer drug sorafenib as major hit that effec-tively kills MRSA strains. Varying the key structural features led to the identification of a potent analogue, PK150, that showed antibacterial activity against several pathogenic strains at submicromolar concentrations. Furthermore, this antibiotic eliminated challenging persisters as well as established biofilms. PK150 holds promising therapeutic potential as it did not induce in vitro resistance, and shows oral bioavailability and in vivo efficacy. Analysis of the mode of action using chemical proteomics revealed several targets, which included interference with menaquinone biosynthesis by inhibiting demethylmenaquinone methyltrans-ferase and the stimulation of protein secretion by altering the activity of signal peptidase IB. Reduced endogenous menaquinone levels along with enhanced levels of extracellular proteins of PK150-treated bacteria support this target hypothesis. The associ-ated antibiotic effects, especially the lack of resistance development, probably stem from the compound’s polypharmacology.en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleMethods for characterizing, applying, and teaching CRISPR-Cas systems.en_US
dc.typeArticleen_US
dc.contributor.departmentHIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.en_US
dc.identifier.journalMethodsen_US
dc.source.journaltitleMethods (San Diego, Calif.)


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Attribution-NonCommercial-ShareAlike 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International