Loading...
Methods for characterizing, applying, and teaching CRISPR-Cas systems.
Beisel, Chase L
Beisel, Chase L
Citations
Altmetric:
Advisors
Editors
Other Contributors
Issue Date
2020-01-16
Submitted date
Files
Loading...
Beisel.pdf
Adobe PDF, 130.82 KB
Other Titles
Abstract
New 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.
Citation
Methods. 2020 Jan 16. pii: S1046-2023(20)30020-7. doi: 10.1016/j.ymeth.2020.01.004.
Publisher
Journal
PubMed ID
PubMed Central ID
Additional Links
Embedded video
Type
Article
Language
en
Description
Series/Report no.
ISSN
1095-9130
EISSN
ISBN
ISMN
Gov't Doc #
Sponsors
License
Attribution-NonCommercial-ShareAlike 4.0 International