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Antimicrob Agents Chemother. 2018 Dec 21;63(1). pii: e01585-18. doi: 10.1128/AAC.01585-18. Print 2019 Jan.

A Novel Actin Binding Drug with In Vivo Efficacy.

Author information

1
Department of Biology, Texas A&M University, College Station, Texas, USA.
2
Department of Chemistry and Biochemistry, CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, Texas, USA.
3
Department of Chemistry, Natural Products LINCHPIN lab, Texas A&M University, College Station, Texas, USA.
4
Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, Starkville, Mississippi, USA.
5
Department of Biological Sciences, Mississippi State University, Mississippi State, Mississippi, USA.
6
Department of Biological Sciences, Mississippi State University, Mississippi State, Mississippi, USA gordon@biology.msstate.edu jsmith@bio.tamu.edu.
7
Center for Medical Mycology, University Hospitals of Cleveland/Case Western Reserve University, Cleveland, Ohio, USA.
8
Department of Biology, Texas A&M University, College Station, Texas, USA gordon@biology.msstate.edu jsmith@bio.tamu.edu.

Abstract

Occidiofungin is produced by the soil bacterium Burkolderia contaminans MS14 and is structurally similar or identical to the burkholdines, xylocandins, and cepacidines. This study identified the primary cellular target of occidiofungin, which was determined to be actin. The modification of occidiofungin with a functional alkyne group enabled affinity purification assays and localization studies in yeast. Occidiofungin has a subtle effect on actin dynamics that triggers apoptotic cell death. We demonstrate the highly specific localization of occidiofungin to cellular regions rich in actin in yeast and the binding of occidiofungin to purified actin in vitro Furthermore, a disruption of actin-mediated cellular processes, such as endocytosis, nuclear segregation, and hyphal formation, was observed. All of 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 may fill the existing gap in treatment options for fungal infections or different types of cancer.

KEYWORDS:

actin binding proteins; anticancer therapy; antifungal therapy; candidiasis; occidiofungin

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