Transformation from Hydrophilic Yet Membrane-Inactive Linear Chain Polymers to Membrane-Active Nanoantibiotics

Although amphipathic membrane-active antimicrobials (MAAs) have the potential to thwart antimicrobial resistance (AMR), their clinical translation is challenging because the same hydrophobic interactions that disrupt bacterial membranes would also impartially debilitate mammalian cells. Herein, we demonstrate that assembly of hydrophilic linear chain polymers into star-shaped nanostructures creates locally concentrated multivalent interactions to pinch microbial membranes, which, together with the negative-curvature lipids rich in microbial membranes eventually induce a topological transition of the membranes to form pores beyond a critical multivalency (e.g., 6-arms). Our work illustrates a facile blueprint of building MAAs from hydrophilic and biocompatible polymers to selectively kill bacteria, including clinical AMR strains with low toxicity.