Globally, fungal pathogens afflict millions of individuals, as shown by the recent Mucormycosis outbreak in India. Studies reveal widespread drug resistance within these pathogens, with the emergence of multi-drug resistance posing a significant challenge. Recognizing this escalating public health burden, the World Health Organization (WHO) has recently emphasized the need for targeted research in this domain. The current antifungal arsenal comprises only three major drug classes: azoles, polyenes, and echinocandins. Unfortunately, these agents demonstrate limitations in controlling fungal infections and developing novel antifungal drugs is challenging. Alternative strategies, such as drug repurposing and combination therapy, are actively explored. Several studies have identified antifungal activity in antibacterial agents, non-steroidal anti-inflammatory drugs (NSAIDs), and immunosuppressants like calcineurin inhibitors. However, drug combinations can interact, exhibiting synergistic, antagonistic, or additive effects.
This study investigates the interactions of repurposed antifungal drugs with conventional antifungals. Preliminary data suggest strain-specific responses to the same drug combinations. We hypothesize that there could be genetic factors that control the fungal response to these drug combinations. To test this hypothesis, we will screen 1,000 genotypically and phenotypically diverse Saccharomyces cerevisiae strains against various antifungal agents, repurposed drugs, and their combinations. High-throughput phenotyping will reveal changes in drug-drug interaction patterns. Furthermore, genome-wide association studies (GWAS) will be conducted to identify genetic determinants influencing these interactions. Additionally, transcriptomics studies will explore the mechanism behind the interaction patterns of these repurposed drugs with established antifungal drugs. This comprehensive investigation aims to elucidate 1) the interactions between repurposed drugs and conventional antifungals, 2) the genetic factors influencing these interactions, and 3) the mechanism behind these drug-drug interactions. Ultimately, this project seeks to empower clinicians to design personalized antifungal regimens that consider co-administered medications and the pathogen's genotype.