Poly(imidazolium ester) antibiotic forms intracellular polymer-nucleic acid biomolecular condensates and fight drug-resistant bacteria

Drug resistance in bacteria is a major problem that calls for new classes of antimicrobial drugs. We report a biodegradable poly(imidazolium ester) (PIE), P8, with excellent broad-spectrum antibacterial activity, high therapeutic selectivity, and an unexploited mechanism of action. P8, a short oligomer, translocates across bacterial membrane and phase separates with intracellular nucleic acids, forming biomolecular condensates. P8 binds the DNA minor groove and intercalates with DNA, interacting with it via electrostatic and hydrogen-bonding interactions. The phase separation of nucleic acids modulated by P8 inhibits in vitro transcription, thereby impeding translation and potentially leading to cell death. Bacterial cytological profiling indicates that the antimicrobial mechanism of P8 differs from those of conventional antibiotics, though it also suggests that P8 may inhibit RNA synthesis. P8 is safe and effective against drug-resistant bacteria in murine models of systemic, intramuscular, and lung infections. This study shows the great potential of intracellular biomolecular condensate formation for combating drug-resistant bacteria.