title: 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: Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, E136, Evanston, IL, 60208, United States of America.
authors: Ann M
authors: AM
authors: Czyzewski
authors: Centre for Microbial Diseases and Immunity Research, #232-2259 Lower Mall Research Station, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.|Dept. of Science, Systems & Models, Roskilde University, Universitetsvej 1, DK-4000, Roskilde, Denmark.
authors: Håvard
authors: H
authors: Jenssen
authors: Centre for Microbial Diseases and Immunity Research, #232-2259 Lower Mall Research Station, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors: Christopher D
authors: CD
authors: Fjell
authors: Centre for Microbial Diseases and Immunity Research, #232-2259 Lower Mall Research Station, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors: Matt
authors: M
authors: Waldbrook
authors: Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, E136, Evanston, IL, 60208, United States of America.
authors: Nathaniel P
authors: NP
authors: Chongsiriwatana
authors: Centre for Microbial Diseases and Immunity Research, #232-2259 Lower Mall Research Station, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors: Eddie
authors: E
authors: Yuen
authors: Centre for Microbial Diseases and Immunity Research, #232-2259 Lower Mall Research Station, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors: Robert E W
authors: RE
authors: Hancock
authors: Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, E136, Evanston, IL, 60208, United States of America.
authors: Annelise E
authors: AE
authors: Barron
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D034444:Peptoids / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D034444:Peptoids