Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

New drugs are desperately needed to combat methicillin-resistant Staphylococcus aureus (MRSA) infections. Here we report screening commercial kinase inhibitors for anti-bacterial activity and found the anti-cancer drug sorafenib as major hit effectively killing MRSA strains. Varying the key structural features led to the identification of a potent analogue, PK150, that showed anti-bacterial activity against several pathogenic strains at sub-micromolar 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, shows oral bioavailability and in vivo efficacy. Analysis of the mode of action using 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 target hypothesis. The associated antibiotic effects, especially the lack of resistance development, likely stem from the compound’s polypharmacology.