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

• Published in: Journal of medicinal chemistry Vol. 64; no. 14; pp. 10429 - 10444
• Main Authors: Liu, Jiayong, Li, Hongxia, Li, Haizhou, Fang, Shanfang, Shi, Jinguo, Chen, Yongzhi, Zhong, Rongcui, Liu, Shouping, Lin, Shuimu
• Format: Journal Article
• Language: English
• Published: American Chemical Society 22-07-2021
• ISSN: 0022-2623; 1520-4804
• 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 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.