Development of membrane-targeting honokiol derivatives as antibacterial agents against gram-positive bacteria

The escalating challenge of multidrug-resistant bacterial infections necessitates the urgent development of new therapeutic agents. To address this, we designed and synthesized a series of novel amphiphilic derivatives through rational modification of the natural product honokiol. Among them, compound 10b demonstrated potent in vitro antibacterial potency against Gram-positive bacteria (MICs = 1-4 μg/mL), coupled with negligible hemolytic activity (HC₅₀ = 106.90 μg/mL) and low cytotoxicity (CC₅₀ = 19.25 μg/mL). 10b also exhibited rapid bactericidal action, low propensity for resistance development, good plasma stability, and efficacy in inhibiting biofilm formation and disrupting mature biofilms. Mechanistic studies revealed that 10b specifically targeted anionic phosphatidylglycerol. This primary interaction led to membrane depolarization and increased permeability, triggering a cascade of downstream effects including the accumulation reactive oxygen species and the leakage of cytoplasmic contents, ultimately resulting in rapid bacterial death. Notably, compound 10b exhibited superior in vivo antibacterial efficacy compared with vancomycin. These findings established 10b as a promising, membrane-targeting lead candidate to overcome the antibiotic resistance crisis.