Uncharted territories in the discovery of antifungal and antivirulence natural products from bacteria

Many fungi can cause deadly diseases in humans, and nearly every human will suffer from some kind of fungal infection in their lives. Only few antifungals are available, and some of these fail to treat intrinsically resistant species and the ever-increasing number of fungal strains that have acquired resistance. In nature, bacteria and fungi display versatile interactions that range from friendly co-existence to predation. The first antifungal drugs, nystatin and amphotericin B, were discovered in bacteria as mediators of such interactions, and bacteria continue to be an important source of antifungals. To learn more about the ecological bacterial-fungal interactions that drive the evolution of natural products and exploit them, we need to identify environments where such interactions are pronounced, and diverse. Here, we systematically analyze historic and recent developments in this field to identify potentially under-investigated niches and resources. We also discuss alternative strategies to treat fungal infections by utilizing the antagonistic potential of bacteria to target fungal stress pathways and virulence factors, and thereby suppress the evolution of antifungal resistance.