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21Current antifungal treatment options are plagued with rapidly increasing occurrence of 22 resistance, high degree of toxicity and a limited spectrum of activity. The need to develop a novel 23 antifungal with a unique target, wider spectrum of activity, and reduced toxicity to the host, is 24 urgent. We have identified and characterized one such compound named occidiofungin that is 25 produced by the soil bacterium Burkholderia contaminans MS14. This study identifies the primary 26 cellular target of the antifungal, which was determined to be actin. Actin binding metabolites are 27 generally characterized by their ability to inhibit polymerization or depolymerization of actin 28 filaments, which presumably accounts for their severe toxicity. Occidiofungin, instead, has a 29 subtler effect on actin dynamics that triggers apoptotic cell death. We were able to demonstrate 30 the effectiveness of the antifungal in treating a vulvovaginal yeast infection in a murine model. 31 This discovery puts occidiofungin in a unique class of actin-binding antifungal compounds with 32 minimal reported toxicity to the host. The results of this study are important for the development 33 of a novel class of antifungals that could fill the existing gap in treatment options for fungal 34 infections. 35 36 37Author summary 38 Widespread resistance to antifungal compounds currently in use has been alarming. 39 Identification and development of a new class of antifungals with a novel cellular target is 40 desperately needed. This study describes the assays carried out to determine the molecular target 41 and evaluate efficacy of one such novel antifungal compound called occidiofungin. Occidiofungin 42 modified with a functional alkyne group enabled affinity purification assays and localization 3 43 studies in yeast. These studies led to the identification of the actin binding property of 44 occidiofungin. Actin-binding by secondary metabolites often exhibit severe host toxicity, but this 45 does not appear to be the case for occidiofungin. We have previously been able to administer 46 occidiofungin to mice at concentrations in the range of 5 mg/kg without any serious complications. 47 We were able to demonstrate the effectiveness of the antifungal in treating a vaginal fungal 48 infection in a murine model. The results outlined in this manuscript establish that occidiofungin is 49 an efficacious compound with a novel molecular target, putting it in a completely new class of 50 antifungals. 51 52 53Fungal infections caused by pathogens that are resistant to commonly used classes of 54 antifungals are becoming increasingly prevalent. Recently, a CDC report described the spread of 55 multi-drug resistant Candida auris causing systemic infections in hospitalized patients [1]. 56 Furthermore, other species such as Candida glabrata and Candida parapsilosis have been reported 57 to have gained resistance to routinely used azoles and echinocandins [2][3][4]. An example of a fungal 58 infection that is rapidly de...

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