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Stimulation of superoxide production increases fungicidal action of miconazole against Candida albicans biofilms

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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.
Keywords
ZINC PYRITHIONE, SUSCEPTIBILITY, EFFLUX PUMPS, OXIDATIVE STRESS, VAGINAL CANDIDOSIS, GENE-EXPRESSION DATA, ANTIFUNGAL AGENTS, FLUCONAZOLE RESISTANCE, SACCHAROMYCES-CEREVISIAE, MECHANISM

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Chicago
De Cremer, Kaat, Katrijn De Brucker, Ines Staes, Annelies Peeters, Freija Van den Driessche, Tom Coenye, Bruno PA Cammue, and Karin Thevissen. 2016. “Stimulation of Superoxide Production Increases Fungicidal Action of Miconazole Against Candida Albicans Biofilms.” Scientific Reports 6.
APA
De Cremer, Kaat, De Brucker, K., Staes, I., Peeters, A., Van den Driessche, F., Coenye, T., Cammue, B. P., et al. (2016). Stimulation of superoxide production increases fungicidal action of miconazole against Candida albicans biofilms. SCIENTIFIC REPORTS, 6.
Vancouver
1.
De Cremer K, De Brucker K, Staes I, Peeters A, Van den Driessche F, Coenye T, et al. Stimulation of superoxide production increases fungicidal action of miconazole against Candida albicans biofilms. SCIENTIFIC REPORTS. 2016;6.
MLA
De Cremer, Kaat, Katrijn De Brucker, Ines Staes, et al. “Stimulation of Superoxide Production Increases Fungicidal Action of Miconazole Against Candida Albicans Biofilms.” SCIENTIFIC REPORTS 6 (2016): n. pag. Print.
@article{8059806,
  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.},
  articleno    = {27463},
  author       = {De Cremer, Kaat and De Brucker, Katrijn and Staes, Ines and Peeters, Annelies and Van den Driessche, Freija and Coenye, Tom and Cammue, Bruno PA and Thevissen, Karin},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keyword      = {ZINC PYRITHIONE,SUSCEPTIBILITY,EFFLUX PUMPS,OXIDATIVE STRESS,VAGINAL CANDIDOSIS,GENE-EXPRESSION DATA,ANTIFUNGAL AGENTS,FLUCONAZOLE RESISTANCE,SACCHAROMYCES-CEREVISIAE,MECHANISM},
  language     = {eng},
  pages        = {14},
  title        = {Stimulation of superoxide production increases fungicidal action of miconazole against Candida albicans biofilms},
  url          = {http://dx.doi.org/10.1038/srep27463},
  volume       = {6},
  year         = {2016},
}

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