Abstract
We performed a whole-transcriptome analysis of miconazole-treated Candida albicans biofilms, using RNA-sequencing. Our aim was to identify molecular pathways employed by biofilm cells of this pathogen to resist action of the commonly used antifungal miconazole. As expected, genes involved in sterol biosynthesis and genes encoding drug efflux pumps were highly induced in biofilm cells upon miconazole treatment. Other processes were affected as well, including the electron transport chain (ETC), of which eight components were transcriptionally downregulated. Within a diverse set of 17 inhibitors/inducers of the transcriptionally affected pathways, the ETC inhibitors acted most synergistically with miconazole against C. albicans biofilm cells. Synergy was not observed for planktonically growing C. albicans cultures or when biofilms were treated in oxygen-deprived conditions, pointing to a biofilm-specific oxygen-dependent tolerance mechanism. In line, a correlation between miconazole’s fungicidal action against C. albicans biofilm cells and the levels of superoxide radicals was observed, and confirmed both genetically and pharmacologically using a triple superoxide dismutase mutant and a superoxide dismutase inhibitor N-N′-diethyldithiocarbamate, respectively. Consequently, ETC inhibitors that result in mitochondrial dysfunction and affect production of reactive oxygen species can increase miconazole’s fungicidal activity against C. albicans biofilm cells.
Highlights
We performed a whole-transcriptome analysis of miconazole-treated Candida albicans biofilms, using RNA-sequencing
By targeting particular miconazole-affected pathways identified via this transcriptomic approach we successfully identified compounds that increase the sensitivity of the C. albicans biofilm cells to miconazole
In order to find pathways and processes involved in generating tolerance of C. albicans biofilm cells against miconazole, we performed a genome-wide transcriptome analysis of C. albicans SC5314 biofilms treated with miconazole
Summary
We performed a whole-transcriptome analysis of miconazole-treated Candida albicans biofilms, using RNA-sequencing. The major fungal pathogen of humans, has the capacity to form biofilms on biotic surfaces throughout the human gastro-intestinal tract and genital area While this fungus can cause life-threatening invasive infections in immunocompromised patients, many more individuals are confronted with superficial mucosal infections. This inhibitory effect is augmented by the accumulation of toxic ergosterol precursors[5] Some azoles such as miconazole, induce accumulation of reactive oxygen species (ROS) in planktonic and biofilm fungal cells[6,7,8,9,10,11,12]. In contrast to other azole-type antifungals, a fungicidal effect of ROS-inducing miconazole against biofilms of several C. albicans strains was reported when used in high (millimolar) concentrations[10,11], but the causal relationship between induction of ROS and fungicidal activity remains under debate[13,14]. (at lower concentrations) of miconazole against C. albicans biofilm cells, which is highly desirable in the context of developing novel biofilm eradication strategies
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