Antifungal drug screening: thinking outside the box to identify novel antifungal scaffolds

Invasive fungal infections are responsible for a significant disease burden worldwide. Drugs to treat these infections are limited to only four unique classes, and despite these available treatments, mortality rates remain unacceptably high. In this review, we will discuss antifungal drug screening and how the approach to identifying novel compounds needs move away from traditional growth-based assays in order to meet the demand for new drugs. We highlight specific examples of creative screening strategies that increase the likelihood of identifying compounds with desired activities and provide perspective to inspire development of novel screens for the identification of first-in-class antifungals.