Development of Image Based Profiling for Antifungal Discovery

Project Summary Invasive fungal infections are a leading cause of death in patients with compromised immune systemsWith amortality rateinvasive aspergillosisIAdue primarily to the fungus Aspergillus fumigatussurpasses invasive candidiasis as the most frequent fungal cause of deathSuccessful therapy for IA with the current antifungal armamentarium is notoriously difficultLimitations of the three major approved classes of drugs include inadequate clinical efficacylack of activity against increasingly resistant strainsantifungal toxicitydrug interactionsand requirements of therapeutic drug monitoringThusinnovative agents that exploit novel targets for enhanced efficacy and are also active against resistant strains are critically neededRecent work demonstrates that cytological profiling is a useful tool for antifungal discoveryCytological profiling relies upon measuring a large number of cellular parameters of individual cells using fluorescence microscopyLinnaeus Bioscience Incis a start up company founded to develop and commercialize new drug discovery technologiesincluding cytological profiling technologiesand make them accessible to the pharmaceutical industry and the scientific communityThe goal of this project is to extend our expertise in performing quantitative microscopy with microbial cells to Fungal Cytological ProfilingFCPand develop a robust platform that will allow it to realize its potential in the drug discovery pipeline to more rapidly characterizeidentify and prioritize lead antifungal moleculesIn collaboration with Amplyx Pharmaceuticals Incwe will focus on developing the technology for two key pathogens for which there is currently a great unmet medical needCandida albicans and Aspergillus fumigatusAmplyx will use the information provided by FCP to guide structure activity relationship development in the discovery of new Gwtinhibitors with broad spectrum antifungal activity Project narrative This proposal focuses on developing imaging based technology for rapidly identifying the mechanisms of action of antifungal compoundsThe goal is to develop the technology for two key fungal pathogens and then apply it to a collection of lead antifungal compounds to determine their mechanisms of action