Antimicrobial peptoids containing indole side chains: synthesis, biological activity, and mechanistic study

Abstract

In proteins, tryptophan often leads to strong interactions with biomolecules such as DNAs and phospholipids. Indole side chain in tryptophan can induce both hydrophobic and hydrogen bonding interactions because of the aromatic and -NH functionalities, respectively. In this study, peptoids containing indole side chains were designed to mimic indolicidin, a well-known natural antimicrobial peptide (AMP), that is rich in tryptophan contents and has strong membrane-disruptive activity due to its ability to interact with the membrane interface. Various indole-containing antimicrobial peptoids were synthesized, and their antimicrobial activity was evaluated aiming to overcome the shortcomings of current antimicrobial peptides and peptoids, such as in vivo stability and potential toxicity. The biological assay results suggested that antimicrobial activity was closely related to the degree of hydrophobicity and cationic charge. The selectivity of these peptoids was significantly increased by controlling the number of cationic charges and the degree of helicity because of the strong interaction between the indole and the bacterial membrane. It was found that hydrophobicity was more related to cytotoxicity toward erythrocytes than to antibacterial activity against Escherichia coli. Through counter-ion exchange of selected peptoids, we observed reduced cytotoxicity in peptoids 29 and 32. Our study affords a strategy to increase the selective of cationic amphipathic antimicrobial peptoids through incorporating indole side chains in the specific positions.