Rational Design of Dipicolylamine-Containing Carbazole Amphiphiles Combined with Zn<sup>2+</sup> as Potent Broad-Spectrum Antibacterial Agents with a Membrane-Disruptive Mechanism
Liu JiaYong, Hongxia Li, Haizhou Li, Shanfang Fang, Jinguo Shi, Yongzhi Chen, Rongcui Zhong, Shouping Liu, Shuimu Lin
Abstract
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.