Structure-Activity Relationship Study of Novel Peptoids That Mimic the Structure of Antimicrobial Peptides

The constant emergence of new bacterial strains that resist the effectiveness of marketed antimicrobials has led to an urgent de-mand for and intensive research on new classes of compounds to combat bacterial infections. Antimicrobial peptoids comprise one group of potential candidates for antimicrobial drug development. The present study highlights a library of 22 cationic am-phipathic peptoids designed to target bacteria. All the peptoids share an overall net charge of!4 and are 8 to 9 residues long; however, the hydrophobicity and charge distribution along the abiotic backbone varied, thus allowing an examination of the structure-activity relationship within the library. In addition, the toxicity profiles of all peptoids were assessed in human red blood cells (hRBCs) and HeLa cells, revealing the low toxicity exerted by the majority of the peptoids. The structural optimiza-tion also identified two peptoid candidates, 3 and 4, with high selectivity ratios of 4 to 32 and 8 to 64, respectively, and a concen-tration-dependent bactericidal mode of action against Gram-negative Escherichia coli. Antimicrobial peptides, also known as host defense peptides,are a class of antimicrobial agents that have long served all living organisms in combating infectious diseases by killing or inhibiting the growth of pathogens. As a class, they are relatively short (!100 amino acid residues), positively charged, amphi-pathic (have both hydrophobic and hydrophilic domains), and exhibit various biological activities based on their structural prop