In Vivo,In Vitro,and In Silico Characterization of Peptoids as Antimicrobial Agents |
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Authors: | Ann M. Czyzewski H?vard Jenssen Christopher D. Fjell Matt Waldbrook Nathaniel P. Chongsiriwatana Eddie Yuen Robert E. W. Hancock Annelise E. Barron |
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Affiliation: | 1. Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, E136, Evanston, IL, 60208, United States of America;2. Centre for Microbial Diseases and Immunity Research, #232–2259 Lower Mall Research Station, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;3. Dept. of Science, Systems & Models, Roskilde University, Universitetsvej 1, DK-4000, Roskilde, Denmark;Purdue University, UNITED STATES |
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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. |
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