Feleucin-K3 Analogue with an α-(4-Pentenyl)-Ala Substitution at the Key Site Has More Potent Antimicrobial and Antibiofilm Activities in Vitro and in Vivo

• Published in: ACS infectious diseases 2021-01, Vol.7 (1), p.64-78
• Main Authors: Guo, Xiaomin, Rao, Jing, Yan, Tiantian, Zhang, Bangzhi, Yang, Wenle, Sun, Wangsheng, Xie, Junqiu
• Format: Article
• Language: English
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.0c00545

The development of antimicrobial compounds is now regarded as an urgent problem. Antimicrobial peptides (AMPs) have great potential to become novel antimicrobial drugs. Feleucin-K3 is an α-helical cationic AMP isolated from the skin secretion of the Asian bombinid toad species and has antimicrobial activity. In our previous studies, amino acid scanning of Feleucin-K3 was performed to determine the key site affecting its activity. In this study, we investigated and synthesized a series of analogues that have either a natural or an unnatural hydrophobic amino acid substitution at the fourth amino acid residue of Feleucin-K3. Among these analogues, Feleucin-K59 (K59), which has an α-(4-pentenyl)-Ala substitution, was shown to have increased antimicrobial activity against both standard and drug-resistant strains of clinical common bacteria, improved stability, no hemolytic activity at antimicrobial concentrations, and no resistance. In addition, K59 has potent antibiofilm activity . More importantly, K59 showed better antimicrobial and antibiofilm activities against drug-resistant bacteria in experiments in mice than traditional antibiotics. In this preliminary study of the mechanism of action, we found that K59 could rapidly kill bacteria by a dual-action mechanism of disrupting the cell membrane and binding to intracellular DNA, thus making it difficult for bacteria to develop resistance.