Identification of novel cinnamamide-pyridine quaternary ammonium derivatives as membrane-targeting antibacterial agents against Gram-positive bacteria.

The escalating crisis of antimicrobial resistance necessitates the development of novel antibacterial agents with distinct mechanisms of action. Inspired by the membrane-disruptive properties of antimicrobial peptides, a series of amphiphilic cinnamamide-pyridine quaternary ammonium derivatives were rationally designed and synthesized. The optimal derivative, compound 9c, featuring a bis-cationic scaffold with hexyl chains, exhibited potent and broad-spectrum antibacterial activity against Gram-positive pathogens (MICs = 0.5-1 μg/mL), along with good safety profiles characterized by low hemolytic activity (HC50 = 482.4 μg/mL) and low cytotoxicity (CC50 = 32.92 μg/mL). Other notable attributes included exceptional plasma stability, rapid bactericidal kinetics, a low tendency to induce resistance, and strong antibiofilm activity. Mechanistic investigations revealed that compound 9c selectively target bacterial membranes via specific interaction with phosphatidylglycerol, leading to membrane depolarization, increased permeability, and subsequent leakage of intracellular components. More importantly, 9c significantly reduced bacterial burden and mitigated tissue inflammation, outperforming vancomycin in a murine skin abscess model. Collectively, these findings establish 9c as a promising membrane-active antibacterial candidate worthy of further development.