Cap1p And Reactive Oxygen Species Are Involved In The Development Of Drug Resistance In Candida Albicans

Cap1p, a bZip transcription factor in Candida albicans, has been reported to be involved in oxidative stress and drug resistance, but the underlying mechanism is still unclear. In this study, firstly, we demonstrated that the over-expression of Caplp resulted in the intensive resistance to fluconazole by constructing a Caplp over-expression Candida albicans strain. Secondly, we clarified that Caplp was involved in oxidative stress response through multiple pathways and revealed the biological functions of this transcription factor through microarray analysis and some other molecular biological methods. Thirdly, on the foundation of our previous findings, we proved that the transcription of multidrug resistance gene CaMDRl could be induced by reactive oxygen species (ROS) in a Caplp-dependent manner through Northern blot analysis. Fourthly, we investigated benomyl, a tool drug in the research work of drug resistance in Candida albicans. The results showed that benomyl could increase intracellular ROS and cause oxidative injury on Candida albicans cells;its induction effect on the transcription of CaMDRl could be blocked by antioxidant N-acetylcysteine, which indicated that its effect on CaMDRl transcription was mediated by ROS. Finally, we revealed that various commonly used antifungal drugs (Amphotericin B, Itraconazole, Ketoconazole and Miconazole) could increase intracellular ROS and the combination of antioxidants (Vitamin C and N-acetylcysteine) with antifungals (Amphotericin B, Itraconazole, Ketoconazole, Miconazole, Fluconazole and Terbinafine) could decrease the antifungal effect of the antifungals in vitro. Oxidative injury could be widely involved in the antifungal effect of the antifungals. Generally speaking, our study showed that antifungal drugs increased intracellular ROS, and ROS activated the expression of the drug resistance gene CaMDRl in a Caplp-dependent manner, which could be an important molecular mechanism in the development of drug resistance in Candida albicans.