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In article number https://doi.org/10.1002/advs.201903117, Ji‐Xin Cheng and co‐workers report an endogenous chromophore‐based phototherapy platform to combat antibiotic‐resistance Staphylococcus aureus infections. Functional membrane microdomains of Staphylococcus aureus are catastrophically disrupted via photochemical decomposition of membrane‐bound carotenoid pigment, staphyloxanthin, thus reviving a broad spectrum of conventional antibiotics against Staphylococcus aureus.

Confronted with the rapid evolution and dissemination of antibiotic resistance, there is an urgent need to develop alternative treatment strategies for drug‐resistant pathogens. Here, an unconventional approach is presented to restore the susceptibility of methicillin‐resistant S. aureus (MRSA) to a broad spectrum of conventional antibiotics via photo‐disassembly of functional membrane microdomains. The photo‐disassembly of microdomains is based on effective photolysis of staphyloxanthin, the golden carotenoid pigment that gives its name. Upon pulsed laser treatment, 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, the photolysis approach increases susceptibility and inhibits development of resistance to a broad spectrum of antibiotics including penicillins, quinolones, tetracyclines, aminoglycosides, 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 endogenous chromophore‐targeted phototherapy concept paves a novel platform to revive conventional antibiotics to combat drug‐resistant S. aureus infections as well as to screen new lead compounds., Decomposition of staphyloxanthin, a membrane‐bound yellow pigment in Staphylococcus aureus, by nanosecond pulsed blue laser induces catastrophic disassembly of its functional membrane microdomains. The photo‐disassembly renders membranes permeable and fluidic with important proteins including PBP2a and efflux pump malfunctioned. As a result, photodisassembly of membrane microdomains revives a broad spectrum of conventional antibiotics against Staphylococcus aureus.