Structure-Activity Relationship Study of Antimicrobial Peptide PE2 Delivered Novel Linear Derivatives with Potential of Eradicating Biofilms and Low Incidence of Drug Resistance

The ongoing emergence of antibiotic-resistant pathogenshad beendramatically stimulating and accelerating the need for new drugs.PE2 is a kind of cyclic lipopeptide with broad-spectrum antimicrobialactivity. Herein, its structure-activity relationship wassystematically investigated by employing 4 cyclic analogues and 23linear analogues for the first time. The screened linear analogues 26 and 27 bearing different fatty acyls at N-terminiand a Tyr residue at the 9th position had superior potency comparedto the cyclic analogues and showed equivalent antimicrobial activitycompared with PE2. Notably, 26 and 27 exhibitedsignificant ability against multidrug-resistant bacteria, favorableresistance to protease, excellent performance against biofilm, lowdrug resistance, and high effectiveness against the mice pneumoniamodel. The antibacterial mechanisms of PE2 and linear derivatives 26 and 27 were also preliminarily explored inthis study. As described above, 26 and 27 are promising antimicrobial candidates for the treatment of infectionsassociated with drug-resistant bacteria.

Automated summary

The emergence of antibiotic-resistant pathogens has increased the demand for new drugs. In this study, the structure-activity relationship of PE2, a cyclic lipopeptide with broad-spectrum antimicrobial activity, was investigated. Two linear analogues, 26 and 27, showed superior potency compared to cyclic analogues and exhibited significant antimicrobial activity against multidrug-resistant bacteria.