Monday, May 6, 2024
5/6/2024
PROJECT SUMMARY/ABSTRACT Opportunistic human fungal pathogens cause serious diseases. As resistance to the current arsenal of antifun- gals increases, there is an urgent need to develop new therapeutics. The goals of this application are to elucidate how EntV, a peptide secreted by Enterococcus faecalis that shows promising efficacy in several animal models, inhibits fungal pathogenicity and to develop derivatives with improved stability and activity. The central hypothe- sis is that the hydrophobic nature of one alpha helix of EntV enables binding to a target associated with fungal extracellular vesicles (EVs), interfering with the export of material associated with virulence. The rationale for this research is that identification of the mechanism by which EntV inhibits the virulence of fungal pathogens will lead to new treatment strategies, which are desperately needed. Aim #1 is to identify the characteristics of EntV associated with antifungal activity. Based on recently published data showing that the seventh helix of EntV is the source of antifungal efficacy, it is hypothesized that the hydrophobic nature of this helix is important, and that antifungal efficacy can be improved by changes that increase hydrophobicity and stability. In this aim, a7 will be modified using both random and rational design strategies and tested for antifungal efficacy, initially in biofilm and C. elegans infection models. Promising candidates will be further tested in murine oropharyngeal candidiasis (OPC), murine systemic bloodstream candidiasis, and rat venous catheter infection models. Aim #2 will elucidate the mechanism(s) by which EntV inhibits fungal pathogenesis. Based on preliminary data showing EntV binding to EVs, the working hypothesis for this aim is that EntV disrupts/interferes with the transport of material that promotes fungal virulence. Goals for this aim include characterizing EntV-induced changes in EV number, dis- tribution, and components, identifying the cell envelope component(s) to which EntV binds, and identifying and characterizing strains and mutants that are no longer susceptible to EntV. Because of the serious and growing morbidity, mortality and antimicrobial resistance associated with fungal infections, the investigation will signifi- cantly and positively contribute to human health by providing new avenues for anti-fungal development. Addi- tionally, the study will broadly impact knowledge in the fields of antimicrobial peptides, fungal pathogenesis, EVs, and interkingdom microbial interactions. Finally, an antimicrobial mechanism of action that targets EVs and re- sults in loss of virulence represents a conceptual innovation.
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