Discovery of New Anti-MRSA Agents Based on Phenoxyethanol and Its Mechanism.

Methicillin-resistant (MRSA) poses a severe threat to public health and safety. The discovery and development of novel anti-MRSA drugs with a new mode of action are a challenge. In this study, a class of novel aryloxyethyl propiolates and their homologues as anti-MRSA agents have been designed and synthesized based on phenoxyethanol, of which compound showed high inhibitory activity against MRSA with an MIC of 0.78 μg/mL and an MBC of 3.13 μg/mL, which was better than that of vancomycin. Compound could destroy the cell wall and cell membrane, inhibited the formation of a biofilm, and bound to the DNA of MRSA through the electrostatic and groove interaction. Proteomic and metabolomic studies revealed that compound affected multiple intracellular metabolic pathways of MRSA. Notably, compound could effectively inhibit the expression of CrtPQMN proteins and block the biosynthesis of virulence factor (staphyloxanthin). Thus, aryloxyethyl propiolates and their homologues are promising anti-MRSA agents with multiple targets.