In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents.

Abstract

Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one of the best candidate peptoids at 4 mg/kg significantly reduces with a two-log order the bacterial counts compared with saline-treated controls. Taken together, our results demonstrate the promising therapeutic potential of peptoids as antimicrobial agents.

• Authors: Ann M Czyzewski, Håvard Jenssen, Christopher D Fjell, Matt Waldbrook, Nathaniel P Chongsiriwatana, Eddie Yuen, Robert E W Hancock, Annelise E Barron
• Journal: PloS one (PLoS One) Vol. 11 Issue 2 Pg. e0135961 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 26849681 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Infective Agents
• Antimicrobial Cationic Peptides
• Peptoids

Topics

• Animals
• Anti-Infective Agents (chemistry, pharmacology)
• Antimicrobial Cationic Peptides (chemistry, pharmacology)
• Bacteria (drug effects)
• Bacterial Infections (drug therapy, microbiology)
• Drug Resistance, Bacterial
• Escherichia coli (drug effects)
• Mice
• Microbial Sensitivity Tests
• Molecular Structure
• Peptoids (chemistry, pharmacology)
• Quantitative Structure-Activity Relationship
• Staphylococcus aureus (drug effects)