Identification of novel molecular targets in drug resistant fungi

Abstract

Fungal infections affect billions of people on a global scale and an increase in the more severe invasive fungal infections is observed. This increase is related to the enlarged number of hospitalized patients, including transplant patients and cancer patients. Treatment options for the fungal infections are limited to only a few drug classes, and the most commonly used drugs in the clinic include azoles and echinocandins. However, fungal resistance towards these drugs is an increasing problem and there is an urgent need for new treatment options. This master thesis aims to address the lack of treatments of the drug resistant fungal infections. The approach used to find new treatment options is based on the identification of new molecular targets to use in the therapy of these infections. The method used to identify such targets takes advantage of the possible compensatory mechanisms activated when the fungi acquire resistance towards an antifungal agent. Targeting a possible compensatory protein could contribute to more effective treatment of the fungal infections. Resistance towards echinocandins results from mutations in either FKS1 or FKS2 and identification of new molecular targets to use in treatment are based on negative genetic interactions of these genes. From public available data, a total of 12 genes were validated in this study to have a negative genetic interaction with FKS1 and FKS2. This interaction suggests that these genes could work as potential targets in the treatment of the drug resistant fungal infections and identification of drugs that inhibit the function of these genes could make the therapy more effective. Resistance towards azoles arises due to many different mechanisms and one of them includes the overexpression of certain genes (includes ERG11, UPC2 and PDR3). Similar to the echinocandins, a possible compensatory mechanism activated when the genes are overexpressed would be of interest to target, as this can result in a more effective treatment of the infection. Identification of targets of the azole resistant strains was in this master thesis addressed by performing an SGA screening of S. cerevisiae strains overexpressing UPC2 and PDR3.