A conjugate strategy capable of targeting bacteria and selectively being activated at infection sites
The clinical utility of colistin, a last-resort antibiotic against multidrug-resistant Gram-negative pathogens, is severely constrained by dose-limiting nephrotoxicity (up to 60% incidence) and poor infection-site targeting. Existing prodrug approaches, such as colistin methanesulfonate, rely on slow, non-selective hydrolysis that reduces systemic toxicity but also diminishes antibacterial efficacy at the infection foci. Here we report a conjugate strategy that combines infection-activatable release with bacterial targeting. A series of colistin prodrugs were synthesized by attaching a reactive oxygen species (ROS)-responsive phenylboronic acid linker to all primary amines of colistin, followed by covalent conjugation to sugars via boronic acid–diol complexation. The lead candidate, lactosyl-functionalized colistin prodrug (LaP-Col), exhibited minimal toxicity toward normal tissues and actively targeted bacteria. LaP-Col displayed a maximum tolerated dose exceeding that of colistin by more than 20-fold and minimal nephrotoxicity. In a murine model of Pseudomonas aeruginosa pneumonia, intravenous LaP-Col accumulated in infected lungs, effectively killed bacteria, and significantly improved therapeutic efficacy and survival rates. This prodrug architecture offers a generalizable route to mitigate the inherent toxicity of potent antimicrobial peptides while enhancing site-specific targeting.