Mechanistic Investigation of a Novel Antibiotic Against Multi-Drug Resistant Staphylococcus aureus and Comparative Target Analysis with the Disinfectant Triclocarban

Multi-drug resistant bacteria are a growing threat for human health. In this work, the characterisation of a new antibacterial agent against methicillin-resistant Staphylococcus aureus (MRSA) is described. The molecule, named PK150, emerged from chemical optimisation of the anti-cancer drug sorafenib and is able to kill persister cells, reduce biofilms, and does not induce resistance under laboratory conditions. Detailed mode-of-action analysis using chemical proteomics unveiled two independent protein targets, which are the inhibition of MenG involved in menaquinone biosynthesis and activation of SpsB, a signal peptidase in the secretory pathway. MenG was further found to be a molecular target of the structurally related disinfectant triclocarban, while SpsB activation was confirmed to be an exclusive hallmark of PK150.