期刊
ACS INFECTIOUS DISEASES
卷 8, 期 3, 页码 533-545出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.1c00536
关键词
peptoids; micelles; antibacterial; biofilm; abscess; infection
资金
- NordForsk [82004]
- UiO:Life Science
- Norwegian PhD School of Pharmacy
- Danish Council for Independent Research, Technology and Production [4005-00029]
- U.S. Public Health Services (NIH) [1DP1 OD029517-01]
- UBC Killam Doctoral Scholarship
- Four-Year Fellowship
- CIHR Vanier Graduate Scholarship
- Canadian Institutes for Health Research [FDN-154287]
- Michael Smith Foundation for Health Research [17774]
- University of Otago Research Grant
- Otago Medical Research Foundation Grant [AG388]
- Maxwell Biosciences
- DOE Office of Biological and Environmental Research
- National Institute of Health project ALS-ENABLE [P30 GM124169]
- High-End Instrumentation grant [S10OD018483]
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
Antimicrobial peptides (AMPs) show promise as pharmaceutical candidates for preventing and treating infections caused by multidrug-resistant pathogens. Peptoids, designed as AMP mimics, exhibit antibacterial activity through self-assembly, with different morphologies affecting efficacy.
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-N-substituted 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 activity 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.
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