Holotoxin A 1 from Apostichopus japonicus inhibited oropharyngeal and intra-abdominal candidiasis by inducing oxidative damage in Candida albicans

The holotoxin A , isolated from Apostichopus japonicus, exhibits potent antifungal activities, but the mechanism and efficacy against candidiasis are unclear. In this study we have studied the antifungal effects and mechanism of holotoxin A against Candida albicans and in murine oropharyngeal and intra-abdominal candidiasis. The antifungal effect of holotoxin A against C. albicans was tested in vitro. To explore the antifungal mechanism of holotoxin A , the transcriptome, ROS levels, and mitochondrial function of C. albicans was evaluated. Effectiveness and systematic toxicity of holotoxin A in vivo was assessed in the oropharyngeal and intra-abdominal candidiasis models in mice. Holotoxin A was a potent fungicide against C. albicans SC5314, clinical strains and drug-resistant strains. Holotoxin A inhibited oxidative phosphorylation and induced oxidative damage by increasing intracellular accumulation of ROS in C. albicans. Holotoxin A induced dysfunction of mitochondria by depolarizing the mitochondrial membrane potential and reducing the production of ATP. Holotoxin A directly inhibited the enzymatic activity of mitochondrial complex I and antagonized with the rotenone, an inhibitor of complex I, against C. albicans. Meanwhile, the complex I subunit NDH51 null mutants showed a decreased susceptibility to holotoxin A . Furthermore, holotoxin A significantly reduced fungal burden and infections with no significant systemic toxicity in oropharyngeal and intra-abdominal candidiasis in murine models. Holotoxin A is a promising candidate for the development of novel antifungal agents against both oropharyngeal and intra-abdominal candidiasis, especially when caused by drug-resistant strains.