Vancomycin is primarily used to treat severe infections caused by Gram-positive bacteria and is often considered as the last-resort therapy in the life-threatening situation. However, it is inherently ineffective against Gram-negative bacteria. Herein, we report the design, synthesis, and biological evaluation of novel vancomycin analogues incorporated with lipophilic cationic groups. Through structural optimization and structure-activity relationship (SAR) studies, we identified vancomycin analogue 18b, which exhibited remarkable antibacterial activity against A. baumannii ATCC 17978, with a MIC of 8 μg/mL. In contrast, vancomycin showed no activity against this strain, even at concentration as high as 128 μg/mL. Further investigations revealed that 18b possesses rapid bactericidal properties, low toxicity, and a reduced propensity to induce bacterial resistance. The exceptional antibacterial performance of 18b is partially attributed to the presence of membrane-targeting, lipophilic piperazine cationic groups. In a mouse model infected with A. baumannii ATCC 17978, 18b exhibited excellent efficacy at a dose of 20 mg/kg, while no toxicity was observed. These findings highlight 18b as a promising candidate for further development in the fight against Gram-negative bacterial infections.
