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

ABSTRACT: To combat methicillin-resistant Staphylococcus aureus (MRSA) infections novel drugs addressing unprecedented and resistance-free targets are desperately needed. From a screen of human kinase inhibitors, we find that the anti-cancer drug sorafenib effectively kills MRSA strains. By dissection of the sorafenib scaffold and systematic synthesis of 72 analogs, we identify a potent compound – PK150 – exhibiting a minimal inhibitory concentration of 300 nM against several MRSA strains. 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 good oral bioavailability and in vivo efficacy in a mouse infection model. Mode of action analysis by chemical proteomics revealed several targets including stimulation of protein secretion by signal peptidase IB (SpsB). Enhanced levels of extracellular proteins and resulting imbalances in secreted autolysin levels of PK150-treated bacteria support this target hypothesis. The associated antibiotic effects, especially the lack of resistance development, likely stem from the polypharmacology attribute of the compound. PK150 is therefore the founding member of a new class of highly active antibiotics.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Staphylococcus Aureus Subsp. Aureus Nctc 8325

SUBMITTER: Nina Bach  

LAB HEAD: Stephan A. Sieber

PROVIDER: PXD008070 | Pride | 2022-01-19

REPOSITORIES: Pride