Photoinactivation of catalase sensitizes Candida albicans and Candida auris to ROS-producing agents and immune cells

Nearly all organisms found in nature have evolved and developed their own specific strategies to cope with reactive oxygen species (ROS). Catalase, a heme-containing tetramer protein expressed in a broad range of aerobic fungi, has been utilized as an essential enzymatic ROS detoxifying mechanism, and shows remarkable efficiency in degrading hydrogen peroxide (H2O2) for fungal cell survival and host invasion. Here, we demonstrate that catalase inactivation with blue light renders fungal cells highly susceptible to ROS attack, thus resembling a 9strength-to-weakness optical switch9. To unveil catalase as the underlying molecular target of blue light and its inactivation mechanism, we systematically compared wild-type Candida albicans to a catalase-deficient mutant strain for susceptibility to ROS in the absence/presence of 410 nm treatment. Upon testing on a wide range of fungal species and strains, we found that intracellular catalase could be effectively and universally inactivated by 410 nm blue light. We find that the photoinactivation of catalase in combination with ROS-generating agents is highly effective and potent in achieving full eradication of multiple fungal species and strains, including multiple clinical strains of Candida auris, the causative agent of the global fungal epidemic. In addition, photoinactivation of catalase is shown to facilitate macrophage killing of intracellular Candida albicans. The antifungal efficacy of catalase photoinactivation is further validated using a Candida albicans-induced mouse model of skin abrasion. Taken together, our findings offer a novel catalase-photoinactivation approach to address multidrug-resistant Candida infections.