Title: Self-Assembly of Antimicrobial Peptoids Impacts Their Biological Effects on ESKAPE Bacterial Pathogens

Abstract

Antimicrobial peptides (AMPs) are promising pharmaceutical candidates for the prevention and treatment of infections caused by multidrug-resistant ESKAPE pathogens, which are responsible for the majority of hospital-acquired infections. Clinical translation of AMPs has been limited, in part by apparent toxicity on systemic dosing and by instability arising from susceptibility to proteolysis. Peptoids (sequence-specific oligo-Nsubstituted glycines) resist proteolytic digestion and thus are of value as AMP mimics. Only a few natural AMPs such as LL-37 and polymyxin self-assemble in solution; whether antimicrobial peptoids mimic these properties has been unknown. Here, we examine the antibacterial efficacy and dynamic self-assembly in aqueous media of eight peptoid mimics of cationic AMPs designed to self-assemble and two nonassembling controls. These amphipathic peptoids self-assembled in different ways, as determined by small-angle X-ray scattering; some adopt helical bundles, while others form core–shell ellipsoidal or worm-like micelles. Interestingly, many of these peptoid assemblies show promising antibacterial, antibiofilm activity in vitro in media, under hostmimicking conditions and antiabscess activity in vivo. While self-assembly correlated overall with antibacterial efficacy, this correlation was imperfect. Certain self-assembled morphologies seem better-suited for antibacterial activity. In particular, a peptoid exhibiting a high fraction of long, worm-like micelles showed reduced antibacterial, antibiofilm, and antiabscess activitymore » against ESKAPE pathogens compared with peptoids that form ellipsoidal or bundled assemblies. This is the first report of self-assembling peptoid antibacterials with activity against in vivo biofilm-like infections relevant to clinical medicine.« less

Authors:

Nielsen, Josefine Eilsø  ^[1];

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Alford, Morgan Ashley  ^[2];

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Yung, Deborah Bow Yue ^[3]; Molchanova, Natalia ^[4]; Fortkort, John A. ^[5]; Lin, Jennifer S.  ^[5];

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Diamond, Gill ^[6]; Hancock, Robert E. W.  ^[2];

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Jenssen, Håvard  ^[7];

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Pletzer, Daniel  ^[8];

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Lund, Reidar  ^[9];

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Barron, Annelise E.  ^[5]

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+ Show Author Affiliations

1. Department of Bioengineering, School of Medicine, Stanford University, Stanford, California 94305, United States, Department of Chemistry, University of Oslo, Oslo 0315, Norway
2. Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
3. Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand
4. The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
5. Department of Bioengineering, School of Medicine, Stanford University, Stanford, California 94305, United States
6. Department of Oral Immunology and Infectious Diseases, University of Louisville, School of Dentistry, Louisville, Kentucky 40202, United States
7. Department of Science and Environment, Roskilde University, Roskilde 4000, Denmark
8. Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada, Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand
9. Department of Chemistry, University of Oslo, Oslo 0315, Norway

Publication Date:

Thu Feb 17 00:00:00 EST 2022

Research Org.:

Stanford Univ., CA (United States)

Sponsoring Org.:

USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:

1971543

Alternate Identifier(s):

OSTI ID: 1854552

Grant/Contract Number:  

AC02-05CH1123; AC02-05CH11231

Resource Type:

Published Article

Journal Name:

ACS Infectious Diseases

Additional Journal Information:

Journal Name: ACS Infectious Diseases Journal Volume: 8 Journal Issue: 3; Journal ID: ISSN 2373-8227

Publisher:

American Chemical Society

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; peptoids; micelles; antibacterial; biofilm; abscess; infection; immunology; biofilms; self organization; infectious diseases; antimicrobial agents