Structure–Activity Relationship Study of Antimicrobial Peptide PE2 Delivered Novel Linear Derivatives with Potential of Eradicating Biofilms and Low Incidence of Drug Resistance
Jingying Zhang, Xu Ouyang, Fangyan Zhang, Beibei Li, Linlin Chang, Ping Yang, Wenbo Mao, Sanhu Gou, Yun Zhang, Hui Liu, Jia Yao, Jingman Ni
Abstract
The ongoing emergence of antibiotic-resistant pathogens had been dramatically stimulating and accelerating the need for new drugs. PE2 is a kind of cyclic lipopeptide with broad-spectrum antimicrobial activity. Herein, its structure–activity relationship was systematically investigated by employing 4 cyclic analogues and 23 linear analogues for the first time. The screened linear analogues 26 and 27 bearing different fatty acyls at N-termini and a Tyr residue at the 9th position had superior potency compared to the cyclic analogues and showed equivalent antimicrobial activity compared with PE2. Notably, 26 and 27 exhibited significant ability against multidrug-resistant bacteria, favorable resistance to protease, excellent performance against biofilm, low drug resistance, and high effectiveness against the mice pneumonia model. The antibacterial mechanisms of PE2 and linear derivatives 26 and 27 were also preliminarily explored in this study. As described above, 26 and 27 are promising antimicrobial candidates for the treatment of infections associated with drug-resistant bacteria.