Discovery of novel antifungal candidates for coccidioidomycosis through integrated drug screening and proteomics 2261274

Abstract Introduction Inhalation of airborne Coccidioides species causes coccidioidomycosis, a severe respiratory disease ranked as a significant pathogen by WHO. With infections reaching new records each year, efforts to develop efficient treatments with minimal adverse reactions have been ineffective. This study addresses these gaps by integrating computational and experimental methodologies to discover novel Coccidioides therapeutics and virulence factors. Methods We used computational pipelines to classify 45 Coccidioides-inhibitory chemicals and screened DrugBank and ChEMBL databases based on the chemical grouping of these chemicals to identify drugs for repurposing. In parallel, leveraging California’s botanical diversity, we developed an experimental screening protocol using colorimetric assays and colony forming unit plating to test antifungal drug candidates. To support these drug discovery efforts, we functionally annotated C. immitis hypothetical protein sequences using bioinformatics tools. Comparative analysis with known respiratory fungal virulence factors identified proteases for structural homology analysis and prediction of host immune pathway interactions. Results We revealed ∼9,000 high-quality proteins and identified 300 unannotated proteases as potential therapeutic targets. The experimental screening methodology revealed that locally grown crops provide potent hits, demonstrating the importance of applying local resources to tackle regional problems. Conclusion These approaches provide a foundation for developing improved coccidioidomycosis treatments. Funding Source NIH R15AI174173, NIH T32-GM141862, GEM consortium fellowship Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)