A Novel Actin Binding Drug with In Vivo Efficacy [Mechanisms of Action]

Occidiofungin is produced by the soil bacterium Burkholderia contaminans MS14 likely as an antifungal agent. This study identified the primary cellular target of occidiofungin, which was determined to be actin. Occidiofungin modified with a functional alkyne group enabled affinity purification assays and localization studies in yeast. Occidiofungin has a subtle effect on actin dynamics that triggers an apoptotic cell death. We demonstrate highly specific localization of occidiofungin to cellular regions rich in actin in yeast and binding of occidiofungin to purified actin in vitro. Further, disruption of actin mediated cellular processes such as endocytosis, nuclear segregation, and hyphae formation were observed. All these processes require the formation of stable actin cables, which are disrupted following the addition of a subinhibitory concentration of occidiofungin. We were also able to demonstrate the effectiveness of occidiofungin in treating a vulvovaginal yeast infection in a murine model. The results of this study are important for the development of an efficacious novel class of actin binding drugs that could fill the existing gap in treatment options for fungal infections or in the treatment of different types of cancer.

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