Light-controlled inhibition of Gram-positive bacteria by photoswitchable amphiphilic lipids (PALs)

Amphiphilic lipids are potent membrane-disrupting antibacterials, but their activity cannot normally be modulated after administration. Here we report photoswitchable amphiphilic lipids (PALs) that enable reversible, light-controlled modulation of antibacterial potency through photoinduced changes in molecular conformation. The PALs incorporate azobenzene photoswitches linking quaternary ammonium headgroups to variable alkyl chains, allowing their geometry and membrane affinity to be tuned by trans-cis isomerisation. Systematic studies against multidrug-resistant Gram-positive bacteria revealed a striking, chain-length-dependent photomodulation. Short-chain PALs lost activity upon irradiation, whereas long-chain derivatives became strongly antibacterial in their cis-enriched states, with up to 32-fold reductions in MICs. Molecular dynamics simulations correlated these changes with light-dependent differences in membrane insertion depth and molecular orientation, providing a structural basis for optical control of membrane disruption. These findings establish a mechanistic framework for designing photoswitchable amphiphiles that translate molecular photoisomerisation into controllable biological function, extending the reach of photopharmacology into antibacterial membrane-active agents.