A Novel Strategy to Inhibit Candida glabrata Virulence by Targeting an Essential Fungal Lipid Transfer Protein

PROJECT SUMMARY Candida glabrata is a pathogenic fungus in human infectious disease that has acquired antimicrobial resistance, which contributes to the significant mortality rate of 47% in cases of invasive candidiasis (systemic infection).1–5 To help address this threat, the proposed work investigates a novel strategy for interfering with the lipid signaling pathways required for viability and virulence of Candida glabrata. The proposal rests on: (i) the discovery of a novel class of small molecule inhibitors (SMIs) of four chemotypes directed against the fungal lipid-binding protein SEC14 and (ii) the idea that SEC14 is a compelling target for next-generation antimycotics that offers the capability to interfere with essential phosphoinositide signaling pathways in a specific way that does not involve targeting the highly conserved enzymes of these signaling pathways. Whereas the actions of these SMIs against the SEC14 of Saccharomyces cerevisiae has been studied, there is little information regarding the efficacies of these SMIs in targeting the SEC14 proteins of pathogenic fungi. Candida glabrata provides a direct path to testing the idea that targeting SEC14 is a viable strategy for developing next-generation antimycotic drugs. This project addresses: (i) the antimycotic potential of SEC14-directed SMIs against Candida glabrata, (ii) their potencies, (iii) the biochemical and structural basis for how these SMIs inhibit C. glabrata SEC14 proteins expressed by clinical isolates, (iv) the cellular consequences of SMI treatment in both planktonic and community (biofilm) settings, and (v) their efficacies in inhibiting virulence activities of C. glabrata. Given my career interests in internal medicine, this project will provide a deeper understanding of the approach to drug resistance in infection, a serious clinical problem on the medicine ward.6