Helicity Modulation Improves the Selectivity of Antimicrobial Peptoids

Ho Yeon Nam, Jieun Choi, S. Dinesh Kumar, Josefine Eilsø Nielsen, Minkyu Kyeong, Sungrok Wang, Dahyun Kang, Yunjee Lee, Jiyoun Lee, Myung-Han Yoon, Sukwon Hong, Reidar Lund, Håvard Jenssen, Song Yub Shin*, Jiwon Seo*

*Corresponding author

Research output: Contribution to journalJournal articleResearchpeer-review


The modulation of conformational flexibility in antimicrobial peptides (AMPs) has been investigated as a strategy to improve their efficacy against bacterial pathogens while reducing their toxicity. Here, we synthesized a library of helicity-modulated antimicrobial peptoids by the position-specific incorporation of helix-inducing monomers. The peptoids displayed minimal variations in hydrophobicity, which permitted the specific assessment of the effect of conformational differences on antimicrobial activity and selectivity. Among the moderately helical peptoids, the most dramatic increase in selectivity was observed in peptoid 17, providing more than a 20-fold increase compared to fully helical peptoid 1. Peptoid 17 had potent broad-spectrum antimicrobial activity that included clinically isolated multi-drug-resistant pathogens. Compared to pexiganan AMP, 17 showed superior metabolic stability, which could potentially reduce the dosage needed, alleviating toxicity. Dye-uptake assays and high-resolution imaging revealed that the antimicrobial activity of 17 was, as with many AMPs, mainly due to membrane disruption. However, the high selectivity of 17 reflected its unique conformational characteristics, with differential interactions between bacterial and erythrocyte membranes. Our results suggest a way to distinguish different membrane compositions solely by helicity modulation, thereby improving the selectivity toward bacterial cells with the maintenance of potent and broad-spectrum activity.
Original languageEnglish
JournalACS infectious diseases
Issue number10
Pages (from-to)2732-2744
Number of pages13
Publication statusPublished - 2020

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