There has been increasing concern regarding the emergence of multi-drug resistant pathogens. The resistance develops when pathogens, especially bacteria, are frequently exposed to conventional antibiotics, as they are heavily used in both human and livestock. This is due to the high target specificity of conventional antibiotics, which places pathogens in high selective pressures and eventually results in drug resistant by mutations. To address this issue, global actions and cooperation are needed. At the same time, new technologies and strategies need to be developed. Host defense peptides (HDPs) are widely found in the innate immune system. They show both direct antimicrobial properties and immunomodulatory activities. The multifaceted functions of HPDs make them less likely to promote antimicrobial resistance. Thus, they are promising as new therapeutics to treat multi-drug resistant infections. In fact, several drug candidates derived from HDPs have entered the clinical trial, but none of them got into the clinic. This is due to several challenges associated with HDPs, such as low in vivo stability, high cost of manufacturing, and toxicity to mammalian cells. In this dissertation, we explored the ability of a new type of unnatural scaffolds (gamma-AApeptides) to mimic the functions of HDPs, including both broad spectrum antimicrobial properties and immunomodulatory activities. Furthermore, the efforts to identify simpler and more drug like gamma-AApeptide based antimicrobial agents were also discussed. The findings in this dissertation may lead to the development of potential drug candidates to treat multi-drug resistant infections.
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