Oligopyridinium peptidomimetics with dual bacterial membrane and DNA targeting as resistance-resistant antibacterials.

The serious threat of multidrug-resistant (MDR) bacterial infections necessitates innovative and effective strategies to overcome antibiotic resistance. Although antimicrobial peptidomimetics (AMPMs) have demonstrated significant efficacy in addressing bacterial resistance, challenges such as low target selectivity and high toxicity remain. In an attempt to address such challenges, we designed a series of amidated oligopyridinium peptidomimetics that could target both bacterial membranes and DNA selectively over human cells. A lead compound, 1c, exhibited potent broad-spectrum antibacterial activity (MIC ≤2 μg/mL) and favorable biosafety. Mechanistic studies revealed that 1c binds to bacterial membrane components (phosphatidylglycerol and lipopolysaccharide), inducing membrane depolarization and perforation, while also selectively interacting with bacterial DNA, triggering ROS accumulation and metabolic suppression in bacterial cells. 1c can eradicate both dormant and persistent bacteria within 2 h and maintain efficacy in bacterial infection models involving sheep blood and mammalian cells. 1c showed no toxicity in Galleria mellonella larvae, zebrafish, or mice at 20 mg/kg. In vivo, it reduced bacterial loads, achieving 55 % survival in G. mellonella and 75 % survival in a murine MRSA infection model. This study demonstrates that the newly developed oligopyridinium derivatives are potent dual-targeting antimicrobial agents and may offer a promising strategy to combat MDR infections.