Rational Design of Dipicolylamine-Containing Carbazole Amphiphiles Combined with Zn²⁺ as Potent Broad-Spectrum...

Antibiotic resistance has become one of the most urgently important problems facing healthcare providers. A novel series of dipicolylamine-containing carbazole amphiphiles with strong Zn²⁺ chelating ability were synthesized, biomimicking cationic antimicrobial peptides. Effective broad-spectrum 16 combined with 12.5 μg/mL Zn²⁺ was identified as the most promising antimicrobial candidate. 16 combined with 12.5 μg/mL Zn²⁺ exhibited excellent antimicrobial activity against both Gram-positive and Gram-negative bacteria (MICs = 0.78-3.125 μg/mL), weak hemolytic activity, and low cytotoxicity. Time-kill kinetics and mechanism studies revealed 16 combined with 12.5 μg/mL Zn²⁺ had rapid bacterial killing properties, as evidenced by disruption of the integrity of bacterial cell membranes, effectively preventing bacterial resistance development. Importantly, 16 combined with 12.5 μg/mL Zn²⁺ showed excellent in vivo efficacy in a murine keratitis model caused by Staphylococcus aureus ATCC29213 or Pseudomonas aeruginosa ATCC9027. Therefore, 16 combined with 12.5 μg/mL Zn²⁺ could be a promising candidate for treating bacterial infections.