Antimicrobial peptoids pass rapidly through bacterial membranes and flocculate ribosomes and DNA: A single-cell fluorescence study.

Authors

Yanyu Zhu, Josefine Eilsø Nielsen, Natalia Molchanova, Mainak Mustafi, Claudine Herlan, Bettina Fleck, Stefan Bräse, Ute Schepers, Kristian Sørensen, Claudia Zielke, Jennifer S Lin, James C Weisshaar, Håvard Jenssen, Annelise E Barron

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 27. Pages e2535920123. Jul 07, 2026. Epub Jun 29, 2026.

Abstract

Certain peptoids designed as mimics of host defense peptides such as LL-37 exhibit potent, broad-spectrum antibacterial, antifungal, antiparasitic, and antiviral activity with minimal cytotoxicity. Previous fixed-cell studies have suggested that the peptoids can pass through bacterial membranes and rapidly kill bacteria by aggregating intracellular macroanions, including ribosomes and DNA. However, the dynamic mechanisms of action of these biomimetic peptoids have remained elusive. We employed single-bacterial-cell, time-resolved fluorescence microscopy, and single-particle tracking methods to investigate the effects of the 12mer peptoid TM1, along with shorter alkylated and brominated analogues, on cytoplasmic membrane permeabilization and DNA and ribosome rigidification of Escherichia coli. Our results demonstrate that TM1 and several of its analogues permeabilize the cytoplasmic membrane within five minutes of flowing the peptoid solution over the cells-faster than seen for the important human antimicrobial peptide LL-37-and rigidify DNA and ribosomes as effectively as LL-37. Detailed biophysical structural and dynamical studies show that TM1 binds to both DNA (double-stranded and single-stranded) and single-stranded RNA in a similar manner to LL-37, which is well known to display strong nucleic acid binding. These results support our hypothesis that TM1 and its analogues exert their antimicrobial effects through intracellular aggregation of biomacromolecules such as ribosomes, RNA, and DNA. TM1 displays a higher affinity for RNA compared to DNA, suggesting it will preferentially bind in vivo to bacterial ribosomes. Our study yields insight into the dynamic effects of antimicrobial peptoids, facilitating their future development as biomimetic anti-infectives, with the additional advantage of protease invulnerability.

PMID:
42372144
Bibliographic data and abstract were imported from PubMed on 30 Jun 2026.

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