Abstract
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.
Published Version
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