Occidiofungin, an actin binding antifungal with in vivo efficacy in a vulvovaginal candidiasis infection

Ravichandran, A.; Geng, M.; Hull, K. G.; Romo, D.; Lu, S.-E.; Albee, A.; Nutter, C.; Gordon, D.; Ghannoum, M. A.; Lockless, S. W.; Smith, L.

doi:10.1101/368720

bioRxiv · 10.1101/368720

Occidiofungin, an actin binding antifungal with in vivo efficacy in a vulvovaginal candidiasis infection

Ravichandran, A.·Geng, M.·Hull, K. G.·Romo, D.·Lu, S.-E.·Albee, A.·Nutter, C.·Gordon, D.·Ghannoum, M. A.·Lockless, S. W.·Smith, L.

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Abstract

Current antifungal treatment options are plagued with rapidly increasing occurrence of resistance, high degree of toxicity and a limited spectrum of activity. The need to develop a novel antifungal with a unique target, wider spectrum of activity, and reduced toxicity to the host, is urgent. We have identified and characterized one such compound named occidiofungin that is produced by the soil bacterium Burkholderia contaminans MS14. This study identifies the primary cellular target of the antifungal, which was determined to be actin. Actin binding metabolites are generally characterized by their ability to inhibit polymerization or depolymerization of actin filaments, which presumably accounts for their severe toxicity. Occidiofungin, instead, has a subtler effect on actin dynamics that triggers apoptotic cell death. We were able to demonstrate the effectiveness of the antifungal in treating a vulvovaginal yeast infection in a murine model. This discovery puts occidiofungin in a unique class of actin-binding antifungal compounds with minimal reported toxicity to the host. The results of this study are important for the development of a novel class of antifungals that could fill the existing gap in treatment options for fungal infections.\n\nAuthor summaryWidespread resistance to antifungal compounds currently in use has been alarming. Identification and development of a new class of antifungals with a novel cellular target is desperately needed. This study describes the assays carried out to determine the molecular target and evaluate efficacy of one such novel antifungal compound called occidiofungin. Occidiofungin modified with a functional alkyne group enabled affinity purification assays and localization studies in yeast. These studies led to the identification of the actin binding property of occidiofungin. Actin-binding by secondary metabolites often exhibit severe host toxicity, but this does not appear to be the case for occidiofungin. We have previously been able to administer occidiofungin to mice at concentrations in the range of 5 mg/kg without any serious complications. We were able to demonstrate the effectiveness of the antifungal in treating a vaginal fungal infection in a murine model. The results outlined in this manuscript establish that occidiofungin is an efficacious compound with a novel molecular target, putting it in a completely new class of antifungals.

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Ravichandran, A., Geng, M., Hull, K. G., Romo, D., Lu, S.-E., Albee, A., Nutter, C., Gordon, D., Ghannoum, M. A., Lockless, S. W., Smith, L.. 2018-07-13. Occidiofungin, an actin binding antifungal with in vivo efficacy in a vulvovaginal candidiasis infection. https://doi.org/10.1101/368720

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