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Biophysical Mechanisms of Host Defense Peptide (HDP) Toxicity as Revealed by a Study of Peptoid Mimics of HDPs
Author(s) -
Barron Annelise E.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.206.2
Subject(s) - peptoid , peptide , chemistry , magainin , cyclic peptide , bacteria , antibacterial peptide , antibacterial activity , biochemistry , antimicrobial peptides , combinatorial chemistry , biophysics , biology , genetics
We are developing and studying biomimetic N ‐substituted glycine oligomers ( peptoids ) with broad‐spectrum antibiotic activity against pathogens, including antibiotic‐resistant strains of Gram‐positive and Gram‐negative bacteria. Peptoids are sequence‐ and length‐specific oligomers with high similarity to peptides, which are made on solid phase and resist proteolysis; they are ideal for applications for which stability is desired. We designed peptoid oligomers to mimic features of the natural host defense peptides magainin and LL‐37: helical, cationic and amphipathic. A study of over 100 sequence variants allowed us to identify peptoids with potency and broad‐spectrum antibacterial activity similar to natural HDPs. The selectivity of antibacterial peptoids and peptides (i.e., their ability to kill bacteria at low‐μM concentrations while causing only tolerable damage to host mammalian cells) correlates with molecular hydrophobicity and amphipathicity as well as with self‐association in solution. We did biophysical mechanistic assays using peptoids with either high or low antibacterial activity and/or either high or low selectivity, along with selective and non‐selective host defense peptides. Comparative vesicle leakage studies, TEM imaging, and soft X‐ray tomography of untreated and treated bacteria yield powerful insight into mechanisms of action for both HDPs and their peptoid mimics.