(390c) Biomimetic Drugs: In Vitro, In Vivo & mechanistic Studies of 5-12mer Antimicrobial & Antiviral Peptoids to Treat Respiratory Infections at the Airway Interface

Growing bacterial resistance to conventional antibiotics has spurred the exploration of bioengineered antimicrobial peptides (AMPs) and analogues as novel anti-infective agents. However, since peptide bioavailability is limited by proteolysis, non-natural AMP mimics are interesting as more robust and biostable antimicrobials, and offer distinct advantages as potential clinical therapeutics. We report here on our experimental exploration of the development of poly-N-substituted glycines (peptoids) as a new class of biomimetic antimicrobial drugs, via multiple approaches including several different in vitro assays and in vivo mouse studies. After studying more than 120 peptoid sequence variants, we identified a number of unique peptoids that exhibit potent, broad-spectrum antibacterial in vitro activity, and which have a unique, biomimetic mechanism of action, similar to that of the human antibacterial peptide LL-37: bacterial rigidification. In our most recent in vivo testing, mice were infected intratracheally with bioluminescent Pseudomonas aeruginosa, then treated by our TM5 peptoid, providing a significant reduction in bacterial loads compared to untreated animals. TM5 peptoid was also well tolerated in the lung by mice. In addition, new super-resolution fluorescence videomicroscopy studies confirm that these peptoids rapidly “rigidify” bacterial cytoplasm, just like natural cathelicidin AMPs (LL-37, cecropin). New experimental results show that like LL-37, as well, our peptoids have antiviral activity against HSV-1 as well. Finally, we have shown via SAXS studies that the activity and potency of cationic, amphipathic TM5 peptoids is enhanced by their self-assembly into stable, ellipsoidal micelles. Taken together, these results show the highly promising potential clinical applicability of these 5-12mer peptoids.