Invasive fungal infections are a leading cause of death in patients with compromised immune systems. With a 40%-60% mortality rate, invasive aspergillosis (IA), due primarily to the fungus Aspergillus fumigatus, surpasses invasive candidiasis as the most frequent fungal cause of death. Successful therapy for IA with the current antifungal armamentarium is notoriously difficult. Limitations of the three major approved classes of drugs include inadequate clinical efficacy, lack of activity against increasingly resistant strains, antifungal toxicity, drug interactions, and requirements of therapeutic drug monitoring. Thus, innovative agents that exploit novel targets for enhanced efficacy and are also active against resistant strains are critically needed. Recent work demonstrates that cytological profiling is a useful tool for antifungal discovery. Cytological profiling relies upon measuring a large number of cellular parameters of individual cells using fluorescence microscopy. Linnaeus Bioscience Inc. is a start-up company founded to develop and commercialize new drug discovery technologies, including cytological profiling technologies, and make them accessible to the pharmaceutical industry and the scientific community. The goal of this project is to extend our expertise in performing quantitative microscopy with microbial cells to Fungal Cytological Profiling (FCP) and develop a robust platform that will allow it to realize its potential in the drug discovery pipeline to more rapidly characterize, identify and prioritize lead antifungal molecules. In collaboration with Amplyx Pharmaceuticals Inc., we will focus on developing the technology for two key pathogens for which there is currently a great unmet medical need, Candida albicans and Aspergillus fumigatus. Amplyx will use the information provided by FCP to guide structure activity relationship development in the discovery of new Gwt1 inhibitors with broad spectrum antifungal activity.
This proposal focuses on developing imaging based technology for rapidly identifying the mechanisms of action of antifungal compounds. The 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.
