Staphylococcus aureusis one of the most common pathogens associated with infected wounds. In combination with disinfection and drainage, a prescription of topical application with conventional antibiotics (e.g., methicillin) is the current standard of care for S. aureus-infected wounds. This treatment has been rendered nearly ineffective by the emergence of resistance, including methicillin-resistant (MRSA) and vancomycin-resistant (VRSA) strains. This study examines use of biomimetic antimicrobial peptoids (poly-N-substituted glycines) as mimics of naturally occurring host defense peptides, as an alternative to treatment with conventional antibiotics. Helical, cationic peptoids showed excellent efficacy against S. aureusin both planktonic and biofilm form. Peptoids impaired existing biofilms, and led to a reduction of new biofilm formation for both methicillin-susceptible S. aureus(MSSA), and MRSA. Our previously well-studied cationic, amphipathic and helical 12mer called Peptoid 1, in particular, at 1.6 µM, detaches existing MRSA biofilms and prevents formation of new biofilms. In comparison, conventional antibiotics were unable to completely detach or prevent biofilm formation at the concentrations tested. In more recent work, we have also tested several different antimicrobial peptoids against a Pan-resistant AR-0666 strain of Klebsiella pneumoniaein a murine abrasion wound model, and found that several different linear and cyclic peptoids showed good activity both in vitroand in vivoagainst this AR-0666 strain, which resists all FDA-approved antibiotics. The mechanism of action of certain antimicrobial peptoids appears to be in line with that recently shown by the Weisshaar laboratory, in which bacterial cells are very rapidly rigidified, as observed by super-resolution fluorescence microscopy, after being treated with antimicrobial peptides like LL-37; the same effect was seen to occur even more rapidly with certain antimicrobial peptoids such as Peptoid 1. We have shown that Peptoid 1 rapidly penetrates through bacterial membranes, enters the cell, and causes the rapid flocculation of bacterial cell contents, into dense biomass aggregates. Bacteria are more susceptible to this biophysical flocculation mechanism of action than mammalian cells.