Combining Miconazole and Domiphen Bromide Results in Excess of Reactive Oxygen Species and Killing of Biofilm Cells

Abstract

Fungal biofilm-related infections are increasingly occurring. We previously identified a fungicidal antibiofilm combination, consisting of miconazole (MCZ) and the quaternary ammonium compound domiphen bromide (DB). DB eliminates tolerance rather than altering the susceptibility to MCZ of various Candida spp. Here we studied the mode of action of the MCZ-DB combination in more detail. We found that DB's action increases the permeability of the plasma membrane as well as that of the vacuolar membrane of Candida spp. Furthermore, the addition of DB affects the intracellular azole distribution. MCZ is a fungicidal azole that, apart from its well-known inhibition of ergosterol biosynthesis, also induces accumulation of reactive oxygen species (ROS). Interestingly, the MCZ-DB combination induced significantly more ROS in C. albicans biofilms as compared to single compound treatment. Co-administration of the antioxidant ascorbic acid resulted in abolishment of the ROS generated by MCZ-DB combination as well as its fungicidal action. In conclusion, increased intracellular MCZ availability due to DB's action results in excess of ROS and enhanced fungal cell killing.

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

“…Next, we explored the potential mechanism underlying the ECON-induced upregulation of ATF3. Indeed, numerous studies have reported that azole antifungal drugs, including ECON, exhibit therapeutic effects by generating excessive intracellular reactive oxygen species (ROS) 28 , 29 . Furthermore, the accumulation of ROS has been linked to an enhanced translocation of NF-E2-related factor 2 (Nrf2) to the nucleus, where this transcription factor binds to the antioxidant response element sequences located in the promoter region of the ATF3 gene, thereby promoting its transcription 30 , 31 , 32 .…”

Transcriptomics-based investigation of molecular mechanisms underlying synergistic antimicrobial effects of AgNPs and Domiphen on the human fungal pathogen Aspergillus fumigatus

“…Domiphen could increase the permeability of membrane due to its surfactant properties ( Tits et al, 2020 ), thereby causing AgNPs easily to enter cells, which could be one of the reasons why domiphen could be a potentiator of AgNPs. In addition, Jana Tits, et al found that domiphen increases intracellular miconazole availability by enhancing azole import and possibly by releasing sequestered miconazole ( Tits et al, 2021 ). Similarly, domiphen could probably affect the intracellular AgNPs distribution to increase the antimicrobial activity of AgNPs, which remains to be determined.…”

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