Potentiation of antimycotics with human-tolerable flavonoids

When someone mentions fungal infections, most people think of athletes foot, nail infections or thrush, which are quite common afflictions. Indeed, with more than one billion cases worldwide each year, fungal infections are even more widespread than, for instance, headache or caries. However, fungi can also cause systemic life-threatening infections that are difficult to treat and, in many cases, even cause the death of affected patients. The importance and impact of severe fungal infections has long been neglected, which has propelled the problem of rising infection numbers and increasing resistance to common antifungal drugs. This is especially concerning, since the arsenal of currently used therapeutics is already very limited: only four different drug classes are presently used for the treatment of such infections, some of which have drastic side effects. Resistance development has further exacerbated the problem with many fungi not responding to standard therapy any more. Thus, it is of great importance to find new therapeutics and treatment options to combat severe fungal infections. Currently, the standard treatment for severe fungal infections consists of a monotherapy with only one antifungal drug. An idea for novel treatment strategies could be the combination of two (or more) different agents to circumvent common obstacles of monotherapies. Specifically, this approach would allow for reduction of effective drug doses, thereby lowering adverse drug side effects and reducing the risk of developing resistance. Moreover, this combinatorial avenue might counteract the response of already resistant fungi and literally recover untreatable infections for treatment. This project aims at identifying novel compounds that could be used in combination with common antifungal medications to boost their antifungal activity and improve the therapeutic outcome. We will focus on flavonoids, a group of bioactive compounds that are naturally found in many plants. Many flavonoids are well known for their beneficial effects on human health and are, in general, well tolerated by humans. Upon identification of an effective combination, we will further investigate how this combination acts on the fungal cell and how it exerts its (lethal) action. This will allow us to also identify putative novel molecular pathways and targets to combat fungal infections. In summary, our project will not only identify innovative therapeutic options through combinatorial approaches but also provide molecular knowledge that may set the course to develop new classes of antifungal medications in the future.