Confronted with the rapid evolution and dissemination of antibiotic resistance, there is an urgent need to develop alternative treatment strategies for drug-resistant S. aureus, especially for methicillin-resistant S. aureus (MRSA). We report a photonic approach to eradicate MRSA through blue-light photolysis of staphyloxanthin (STX), an anti-oxidative carotenoid acting as the constituent lipid of the functional membrane microdomains of S. aureus. Our transient absorption imaging study and mass spectrometry unveil the photolysis process of STX. After effective STX photolysis by pulsed laser, cell membranes are found severely disorganized and malfunctioned to defense antibiotics, as unveiled by membrane permeabilization, membrane fluidification, and detachment of membrane protein, PBP2a. Consequently, our photolysis approach sensitizes MRSA to reactive oxygen species attack and increases susceptibility and inhibits development of resistance to a broad spectrum of antibiotics including penicillins, quinolones, tetracyclines, aminoglyco sides, lipopeptides, and oxazolidinones. The synergistic therapy, without phototoxicity to the host, is effective in combating MRSA both in vitro and in vivo in a mice skin infection model. Collectively, this staphyloxanthin-targeted phototherapy concept paves a novel platform to use conventional antibiotics as well as reactive oxygen species to combat multidrug-resistant S. aureus infections.
