Combating Antimicrobial Resistance with Hydrophilic and Eco-Friendly Membrane-Active Antibiotics Derived from Biological Nanoparticles.

The ever-increasing use of antibiotics and the accumulation of antibiotic waste in ecosystems are expediting antimicrobial resistance (AMR). Our next-generation antibiotics should aim for a different antimicrobial mechanism that is less conducive to AMR, a wider therapeutic window tolerant to drug titration, and a quicker deactivation strategy responsive to environmental stimuli. Membrane-active antimicrobials (MAAs) have the potential to thwart AMR, but the lipophilicity of current MAAs gives rise to their broad-spectrum cytotoxicity. Here, we show that biological nanoparticles, such as cyclodextrin and phytoglycogen, can be transformed into potent MAAs with low cytotoxicity by grafting them with hydrophilic polymer brushes. In service, these hydrophilic nanoantibiotics kill bacteria by inducing pore formation exclusively on microbial membranes rich in negative curvature lipids, a bactericidal mode less likely to incur AMR. After service, they are degraded and deactivated by biomass recycling enzymes that are abundant in ecosystems. This study illuminates a new paradigm to combat AMR with hydrophilic and eco-friendly membrane-active antibiotics derived from biological nanoparticles.