Grant: Discovery Grants Program - Individual

Antimicrobial peptides (AMPs) are currently the subject of significant interest, in part due to their important role in our immune systems and in part due to their potential as novel therapeutics to combat the increasingly serious problem of microbial resistance to conventional antibiotics. However, there are gaps in both our understanding of how these molecules work and in our ability to use them as the basis for better treatments. One such gap results from the fact that the detailed mechanism of AMPs has only been studied in highly simplified systems that only approximate, at best, the much more complex cell envelopes against which the AMPs act. Microbe cell envelopes contain a number of additional components that likely affect how AMPs work and probably contribute to the ability of AMPs to kill microbes at levels that don't harm our own cells. We intend to bridge this gap by developing ways to use high resolution, quantitative techniques, like nuclear magnetic resonance (NMR), to investigate AMPs in whole, intact bacteria and mammalian cells. We will then compare our results to the results in the model systems to better understand how AMP actions are modified by the complexity present in real cells. We will also identify and characterize novel AMPs from cod. The cod genome represents an excellent source of potentially new and interesting antimicrobial peptide motifs, since cod have an underdeveloped adaptive immune system, but are literally swimming in a sea of pathogens and so presumably require especially efficacious AMPs. The anticipated significance of the work includes: supplying a badly needed connection between NMR studies that shed light on the mechanism of AMPs and those conditions under which activity is actually observed; developing new methods that enable the application of NMR to the study of any membrane protein in the context of whole cells; making available information of significance to the AMP community and those involved in cod and other fish breeding programs by identifying and characterizing novel marine AMPs.