Rational Design of Dipicolylamine-Containing Carbazole Amphiphiles Combined with Zn2+ as Potent Broad-Spectrum Antibacterial Agents with a Membrane-Disruptive Mechanism

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 mu g/mL Zn2+ was identified as the most promising antimicrobial candidate. 16 combined with 12.5 mu g/mL Zn2+ exhibited excellent antimicrobial activity against both Grampositive and Gram-negative bacteria (MICs = 0.78-3.125 mu g/mL), weak hemolytic activity, and low cytotoxicity. Time-kill kinetics and mechanism studies revealed 16 combined with 12.5 mu g/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 mu g/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 mu g/mL Zn2+ could be a promising candidate for treating bacterial infections.

Automated summary

The novel series of amphiphiles synthesized in this study showed strong Zn2+ chelating ability and exhibited effective broad-spectrum antimicrobial activity with low hemolytic activity and cytotoxicity. In vivo efficacy was demonstrated in a murine keratitis model, making them promising candidates for treating bacterial infections.