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.

Occidiofungin is a nonribosomally synthesized cyclic peptide having a base mass of 1200 Da. It is naturally produced by the soil bacterium Burkholderia contaminans MS14 and possesses potent broad-spectrum antifungal properties. The mechanism of action of occidiofungin is unknown. Viability, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), reactive oxygen species (ROS) detection, membrane and cell wall stability, and membrane mimetic assays were used to characterize the effect of occidiofungin on yeast cells. Confocal and electron microscopy experiments were used to visualize morphological changes within treated cells. TUNEL and ROS detection assays revealed an increase in fluorescence with increasing concentrations of the antifungal. Yeast cells appeared to shrink in size and showed the presence of 'dancing bodies' at low drug concentrations (1 μg/mL). A screen carried out on Saccharomyces cerevisiae gene deletion mutants in the apoptotic and autophagy pathways identified the apoptotic gene for YCA1, as having an important role in occidiofungin response as cells deleted for this gene exhibit a 2-fold increase in resistance. Results from our experiments demonstrate that the mechanism of action for occidiofungin in yeast is different from that of the common classes of antifungals used in the clinic, such as azoles, polyenes, and echinocandins. Our study also indicates that occidiofungin causes cell death in yeast through an apoptotic mechanism of action.

Replication of chloroplast in plant cells is an essential process that requires co-assembly of the tubulin-like plastid division proteins FtsZ1 and FtsZ2 at mid-chloroplast to form a ring structure called the Z-ring. The Z-ring is stabilized via its interaction with the transmembrane protein ARC6 on the inner envelope membrane of chloroplasts. Plants lacking ARC6 are defective in plastid division and contain only one or two enlarged chloroplasts per cell with abnormal localization of FtsZ: instead of a single Z-ring, many short FtsZ filaments are distributed throughout the chloroplast. ARC6 is thought to be the anchoring point for FtsZ assemblies. To investigate the role of ARC6 in FtsZ anchoring, the mobility of green fluorescent protein-tagged FtsZ assemblies was assessed by single particle tracking in mutant plants lacking the ARC6 protein. Mean square displacement analysis showed that the mobility of FtsZ assemblies is to a large extent characterized by anomalous diffusion behavior (indicative of intermittent binding) and restricted diffusion suggesting that besides ARC6-mediated anchoring, an additional FtsZ-anchoring mechanism is present in chloroplasts.

Occidiofungin, a glyco-lipopeptide obtained from the liquid culture of Burkholderia contaminans MS14, has been identified as a novel fungicide. The natural product was shown to have a minimal amount of toxicity in a previous mouse toxicity study following intraperitoneal and subcutaneous administration. In this study, the toxicity of occidiofungin was evaluated following a 5 mg/kg intravenous tail vein injection. In addition, the toxicity of occidiofungin was evaluated against human fibroblast and cancer cell lines. Weight loss was the most significant observation following intravenous administration of occidiofungin. Histology, hematology, and blood serum chemistry did not reveal any significant signs of toxicity. The activity observed in the in vitro cytotoxicity assay against the cancer cell lines was all below 75 nM concentration of occidiofungin. To date, the potency of occidiofungin against these cancer cell lines is greater than any activity observed against fungi. The findings in this study support the need to further evaluate occidiofungin's chemotherapeutic potential.

Occidiofungin is a non-ribosomally synthesized cyclic lipopeptide, which possesses broad spectrum antifungal properties at sub-micromolar concentrations. This report explores multiple routes of administration, formulation, and toxicity of occidiofungin in mice. Further, infection studies were performed in mice to assess the application of occidiofungin for treating a systemic yeast and an intravaginal yeast infection. Formulations for intravenous and intravaginal administration of occidiofungin were prepared. Pharmacokinetic analyses were performed in a murine model, and an LCMS method was developed and used to quantify occidiofungin in the mouse plasma samples. Toxicology and histopathology analysis of two repeat dose studies using occidiofungin were performed. In these animal models, following an intravenous administration, liposomal formulation of occidiofungin improved the half-life and peak plasma concentration compared to liposomal-free formulation. Two long-term repeat dosing toxicity studies of occidiofungin indicated the absence of toxicity in organ tissues. A systemic yeast and vulvovaginal yeast murine models of infection were performed. Findings in the systemic infection study has revealed limitations in occidiofungin's use that may be alleviated with the development of novel structural analogs or with further formulation studies. The gel formulation of occidiofungin demonstrated improved efficacy in a vulvovaginal candidiasis study as compared to the commercial product Monistat 3™. This report outlines the optimal routes of administration of occidiofungin and demonstrates minimal toxicity following chronic exposure. Further, the results from these studies provides a clear indication for the use of occidiofungin towards the treatment of recurrent vulvovaginal candidiasis (RVVC), which is a serious and clinically relevant issue.