title: Superoxide dismutases are involved in Candida albicans biofilm persistence against miconazole.
abstract: We investigated the cellular mechanisms responsible for the occurrence of miconazole-tolerant persisters in Candida albicans biofilms. Miconazole induced about 30% killing of sessile C. albicans cells at 75 μM. The fraction of miconazole-tolerant persisters, i.e., cells that can survive high doses of miconazole (0.6 to 2.4 mM), in these biofilms was 1 to 2%. Since miconazole induces reactive oxygen species (ROS) in sessile C. albicans cells, we focused on a role for superoxide dismutases (Sods) in persistence and found the expression of Sod-encoding genes in sessile C. albicans cells induced by miconazole compared to the expression levels in untreated sessile C. albicans cells. Moreover, addition of the superoxide dismutase inhibitor N,N'-diethyldithiocarbamate (DDC) to C. albicans biofilms resulted in an 18-fold reduction of the miconazole-tolerant persister fraction and in increased endogenous ROS levels in these cells. Treatment of biofilms of C. albicans clinical isolates with DDC resulted in an 18-fold to more than 200-fold reduction of their miconazole-tolerant persister fraction. To further confirm the important role for Sods in C. albicans biofilm persistence, we used a Δsod4 Δsod5 mutant lacking Sods 4 and 5. Biofilms of the Δsod4 Δsod5 mutant contained at least 3-fold less of the miconazole-tolerant persisters and had increased ROS levels compared to biofilms of the isogenic wild type (WT). In conclusion, the occurrence of miconazole-tolerant persisters in C. albicans biofilms is linked to the ROS-detoxifying activity of Sods. Moreover, Sod inhibitors can be used to potentiate the activity of miconazole against C. albicans biofilms.
authors: Centre of Microbial and Plant Genetics, CMPG, Katholieke Universiteit Leuven, 3001 Heverlee, Belgium.
authors: Anna
authors: A
authors: Bink
authors: Davy
authors: D
authors: Vandenbosch
authors: Tom
authors: T
authors: Coenye
authors: Hans
authors: H
authors: Nelis
authors: Bruno P A
authors: BP
authors: Cammue
authors: Karin
authors: K
authors: Thevissen
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology; D025141:Drug Resistance, Fungal / Q000235:genetics; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008825:Miconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D017382:Reactive Oxygen Species; D008825:Miconazole; D004050:Ditiocarb; D013482:Superoxide Dismutase