Rational design of ivacaftor-derived antimicrobial peptidomimetics: Membrane-targeting strategy enhances broad-spectrum antimicrobial efficacy against MDR pathogens.

Antibiotic resistance poses an escalating global public health threat, underscoring the urgent need for novel antimicrobials to combat multidrug-resistant (MDR) pathogens. This study employed an antimicrobial peptide-mimicking strategy to design and synthesize a series of ivacaftor-based derivatives. The candidate compound 27 was identified because of its remarkable broad-spectrum antibacterial activity (MICs = 0.195-3.125 μg/mL), low hemolytic toxicity (HC50 > 200 μg/mL), high cellular safety (CC50 > 50 μg/mL), and good stability in saline and plasma. Further biological exploration revealed that 27 exerted its rapid bactericidal effects by damaging bacterial cell membranes, resulting in a very low frequency of drug resistance. More crucially, in vivo toxicity studies and murine corneal infection models with Staphylococcus aureus confirmed the low toxicity and potent antibacterial efficacy of 27. In summary, as a novel molecular entity, compound 27 is a valuable broad-spectrum, low-toxicity candidate antibacterial agent capable of combating multidrug-resistant (MDR) bacteria.