Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus

ABSTRACT: To combat methicillin-resistant Staphylococcus aureus (MRSA) infections novel drugs are desperately needed. From a screen, we found that the anti-cancer drug sorafenib effectively kills MRSA strains. By synthetic variation of key structural features, we identified a potent analog, PK150, exhibiting activities against several pathogenic strains at sub-micromolar concentrations. The antibiotic induced rapid killing of S. aureus, including challenging persisters, and eradicated established biofilms. PK150 holds promising therapeutic potential as it did not induce in vitro resistance and exhibited oral bioavailability and in vivo efficacy. Mode of action analysis by chemical proteomics revealed several targets, including interference with menaquinone biosynthesis by inhibiting demethylmenaquinone methyltransferase and 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 hypothesis. The associated antibiotic effects, especially the lack of resistance development, likely stem from the compound’s polypharmacology attribute.

INSTRUMENT(S): Orbitrap Fusion ETD, Q Exactive

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Philipp Le  

LAB HEAD: Stephan A. Sieber

PROVIDER: PXD012946 | Pride | 2019-09-09

REPOSITORIES: Pride