A Novel Actin Binding Drug with In Vivo Efficacy.

Akshaya Ravichandran,Daniel Romo,Mengxin Geng,Christopher Nutter,Mahmoud A Ghannoum,Shi-En Lu,Jing Li,Leif Smith,Kenneth G Hull,Aaron Albee,Donna M Gordon,Steve W Lockless

doi:10.1128/aac.01585-18

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.

Highlights

Occidiofungin is produced by the soil bacterium Burkolderia contaminans MS14 and is structurally similar or identical to the burkholdines, xylocandins, and cepacidines
Strains of Candida albicans, Candida glabrata, and Candida parapsilosis that were resistant to fluconazole and caspofungin were sensitive to occidiofungin
To determine whether occidiofungin impacts other cellular activities linked to actin dynamics, we evaluated the effect of occidiofungin on endocytosis in fission yeast

Summary

Introduction

Occidiofungin is produced by the soil bacterium Burkolderia contaminans MS14 and is structurally similar or identical to the burkholdines, xylocandins, and cepacidines. The rise in candidemia caused by non-albicans Candida spp. and the increase in azole resistance [5,6,7,8,9] are alarming and support the need for new antifungals. Current antifungal treatments lead to abnormal liver and kidney function tests and have limitations with respect to their spectrum of activities and toxicities [18, 19]. These limitations and toxicity problems have created an urgent need to identify antifungal compounds that have a novel mechanism of action [20]. This report describes studies to identify the molecular target of occidiofungin and determine its efficacy in a murine model of vulvovaginal candidiasis

Methods

Results

Conclusion