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

Article abstract of DOI:10.1021/acs.jmedchem.1c00858

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 excellentin vivoefficacy in a murine keratitis model caused byStaphylococcus aureusATCC29213 orPseudomonas aeruginosaATCC9027. Therefore, 16 combined with 12.5 μg/mL Zn²⁺could be a promising candidate for treating bacterial infections.