Preclinical characterization of miconazole potentiators as novel treatment of biofilm-related infections and epilepsy

Various fungal species possess the capacity to form biofilms, which are characterized by their high tolerance against most of the commonly used antimycotics. The genus Candida predominates biofilm associated fungal infections, which can occur in for example the urogenital tract (resulting in e.g. vulvovaginal candidiasis) and on medical devices. The incidence of recurrent oral and vulvovaginal candidiasis is significant and resistance against azoles, the preferred treatment, is occurring. To develop more effective antibiofilm treatments, commercially available antimycotics can be combined with potentiators, that increase their antibiofilm activity. An example of an effective fungicidal antibiofilm combination treatment is miconazole combined with domiphen bromide (MCZ-DB). In this PhD dissertation, the mode of action of the MCZ-DB combination treatment will be investigated, allowing the identification of common and/or molecule-specific targets. To identify and validate the targets and tolerance pathways, multiple approaches, including transcriptome analysis, C. albicans mutant libraries and biochemical assays, will be used. Evolution experiments will be performed to study resistance development against the combination. Consequently, this research will result in a deeper understanding of the molecular mechanisms responsible for the increased tolerance of biofilm cells to miconazole, and in the mode of action of this effective fungicidal antibiofilm combination.