A host defense peptide–mimicking prodrug activated by drug-resistant Gram-negative bacterial infections

The high mortality of drug-resistant Gram-negative bacterial infections and the scarcity of antibiotics against Gram-negative bacteria urgently call for effective antimicrobial agents. Antimicrobial polymers that mimic host defense peptides (HDPs) have been extensively studied, but in the complex in vivo environment, cationic polymers can interact with polyanionic macromolecules and host cells bearing polyanionic membranes, leading to undesired side effects. Here, we report an "acid-responsive antimicrobial polymer prodrug" strategy and performed a proof-of-concept treatment using HDP-mimicking poly(2-oxazoline)s. By protecting the side-chain amines with 2,3-dimethylmaleic anhydride to neutralize the positive charges, the poly(2-oxazoline) prodrug can remain stealthy under physiological conditions but expose these charges to become activated at infection sites. The poly(2-oxazoline) prodrug exhibited high biocompatibility, prolonged blood circulation time, and potent activity against drug-resistant Gram-negative bacteria and biofilms in vitro and did not develop antibacterial resistance. Moreover, the poly(2-oxazoline) prodrug showed strong therapeutic potential for both local and systemic infections. The prodrug displayed potent activity in treating Gram-negative bacteria-associated infections in multiple mouse models, including subcutaneous abscess, neutropenic thigh infection, kidney infection, lung infection, and peritonitis. These results demonstrate the effectiveness of our prodrug strategy to develop potent antibacterial agents.