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.

中文翻译：

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咪康唑和多米芬溴化物的组合会导致活性氧过多并杀死生物膜细胞。

与真菌生物膜相关的感染越来越多。我们之前确定了一种杀菌剂抗生物膜组合，该组合由咪康唑（MCZ）和季铵化合物多米芬溴化物（DB）组成。DB消除了耐受性，而不是改变各种假丝酵母菌对MCZ的敏感性。在这里，我们更详细地研究了MCZ-DB组合的作用方式。我们发现DB的作用增加了假丝酵母的质膜和液泡膜的通透性。此外，DB的添加影响细胞内唑的分布。MCZ是一种杀真菌唑，除了众所周知的对麦角固醇生物合成的抑制作用外，还诱导了活性氧（ROS）的积累。有趣的是，MCZ-DB组合在C中诱导了更多的ROS。与单一化合物处理相比，白色念珠生物膜。抗氧化剂抗坏血酸的共同给药导致废除由MCZ-DB组合产生的ROS及其杀真菌作用。总之，由于DB的作用，增加的细胞内MCZ可用性导致ROS过量和真菌细胞杀伤力增强。