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Peptoids: The Next Generation of Antibiotics?

Nicholas Miliaras, PhD

Bacterial resistance to antibiotics is emerging as a major public health problem. Could structural variants of endogenous antimicrobial peptides provide a solution? Find out...

All organisms make host defense peptides. These are short (no more than 100 amino acids) and positively-charged, allowing them to easily integrate into the membrane bilayer and lyse bacterial cells. They are attractive candidates for antimicrobial drug development, but synthetic host defense peptides are degraded in vivo or upon topical application.

Now, Biljana Mojsoska and Håvard Jenssen of Roskilde University in Denmark and Ronald Zuckermann at the Lawrence Berkeley National Laboratory have created novel peptide-like analogs, or peptoids, that have the same bactericidal capacity as host defense peptides but are much more stable.

A structural projection of a peptoid. Credit: Håvard Jenssen.

“This class of antimicrobials strikes a delicate balance of positive charge and hydrophobicity. Peptoids are a nice platform for this problem since we can take clues from the natural molecules and create structures that have a similar overall size, shape, and distribution of charge,” said Zuckermann.

The group engineered a series of 22 peptoid 9-mers and evaluated them for hydrophobicity and bactericidal activity against strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. They also tested the peptoids for hemolysis and cytotoxicity to human cells, identifying two peptoids that exhibited low human hemolysis and cytotoxicity, as well as broader-spectrum activity against the bacterial strains at lower minimum inhibitory concentrations (MIC).

Although there were some technical challenges in synthesizing the peptoids, the ease of synthesis, low cost, flexibility, and scalability make peptoids promising candidates as antibiotics. “It all comes down to how you want to apply them. Lots of studies have demonstrated synergistic potential between peptoids and conventional drugs. There is also increasing evidence of very potent anti-biofilm effects for these compounds at sub-MIC concentrations,” Jenssen noted. “Additionally, there is an endless list of commercially available amines, the building blocks for peptoid synthesis. This opens up exploring an entire new chemical space with respect to antimicrobial peptide mimics.”


Mojsoska B., Zuckermann R.N., and Jenssen H. Structure-Activity Relationship Study of Novel Peptoids That Mimic the Structure of Antimicrobial Peptides. Antimicrob Agents Chemother. 2015 Jul; 59(7):4112-20. doi: 10.1128/AAC.00237-15. Epub 2015 May 4

Keywords:  antibiotics