Biomimetic Drugs: In Vitro, In Vivo & Mechanistic Studies of 5-12mer Antimicrobial & Antiviral Peptoids to Treat Respiratory Infections

Abstract: 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). Our latest experimental results show that like LL-37, as well, our peptoids have antiviral activity as well.  Taken together, these results show the highly promising potential clinical applicability of these 5-12mer peptoids.

Biography: Annelise E. Barron is the W.M. Keck Associate Professor of Bioengineering at Stanford University, where her research is currently focused on two main topics: (1) biomimicry of host defense peptides and lung surfactant proteins, and (2) elucidating the underlying mechanisms of Alzheimer's dementia, which may well be caused by dysregulation of innate immunity caused by chronic infections.  Dr. Barron was trained as a chemical engineer at the University of Washington and U.C. Berkeley, and was a Pharm. Chem. postdoc with Ken A. Dill (UCSF) and Ronald N. Zuckermann (Chiron Corp.). She has been on the faculty at Stanford since 2007, and prior to that, was on the Chemical & Biological Engineering faculty of Northwestern University in Evanston, IL. She has been awarded the Presidential Early Career Award for Scientists & Engineers (PECASE), the Beckman Young Investigator Award, and the Camille Dreyfus Teacher-Scholar Award, and was the youngest scientist ever to serve on the Scientific Advisory Committee to the Director of the NIH. She has more than 165 publications and an H-index of 44, and serves on the advisory boards of several biotechnology companies.