Antimicrobial peptides (AMPs) are naturally occurring host defense molecules, representing an evolutionarily ancient innate immune mechanism against pathogenic infection. As such, many of these
predominantly cationic and amphipathic peptides have been examined for their potential as anti-infective
agents. AMP families such as the defensins and cathelicidins exhibit broad-spectrum antimicrobial activity
against a wide variety of bacteria, fungi and viruses, predominantly by disruption of the microbial
membrane. Due to this physical mechanism, development of resistance by the pathogen is rare. Thus, they
represent a great potential for a new type of anti-infective agent. However, due to a variety of reasons,
including protease sensitivity and poor bioavailability, they have not been developed into actual
therapeutics. To circumvent these issues, we have examined the potential for small molecule mimetics of
AMPs, which would be protease resistant, and have better bioavailability. We previously demonstrated
activity of one such class of mimetics, sequence-specific N-substituted glycine oligomers, or peptoids,
against the human viral pathogen Herpes Simplex Virus-1 (HSV-1), as well as some bacteria. Here we
compare the activity, both in vitro and in vivo, of select peptoids against bacteria, fungi and viruses, to
begin to study the structure/activity relationship with a broad spectrum of microbial pathogens. Our
results show that some peptoid structures are more active against one type of pathogen than another.
However, at least two of the tested peptoids exhibit potent activity against Gram+ bacteria, Grambacteria,
fungi and viruses. Our result suggest that these molecules can be developed into potent broadspectrum
antimicrobial agents.