Sub-lethal concentrations of chlorhexidine inhibit Candida albicans growth by disrupting ROS and metal ion homeostasis

Candida albicans is a normal resident of the human oral cavity. It is also the most common fungal pathogen, causing various oral diseases, particularly in immunocompromised individuals. Chlorhexidine digluconate (CHG) is a broad-spectrum antimicrobial agent widely used in dental practice and has been recommended to treat oral candidiasis. However, its action mechanism against the fungal pathogen C. albicans remains poorly understood. The aim of the present study was to investigate the effect of CHG at sub-lethal concentrations against C. albicans. CHG inhibited the growth of C. albicans in a dose- and time-dependent manner. Cells treated with CHG exhibited altered membrane permeability, reduced metabolic activity, and enhanced metal ion and reactive oxygen species (ROS) accumulation. Copper-sensing transcription factor Mac1, iron-sensing transcription factors Sfu1 and Sef2, and copper transporter Ctr1 regulated intracellular metal ion and ROS homeostasis in response to CHG. Deletion of MAC1, SFU1, or SEF2 increased intracellular ROS production and cell susceptibility to CHG. This study revealed a novel mechanism by which CHG induced apoptosis of C. albicans cells through the disruption of metal ion and ROS homeostasis, which may help to identify new targets for fungal infections.