The antifungal occidiofungin triggers an apoptotic mechanism of cell death in yeast.

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.

Occidiofungin's chemical stability and in vitro potency against Candida species.

Occidiofungin is a cyclic glyco-lipopeptide produced by Burkholderia contaminans. MICs against Candida species were between 0.5 and 2.0 µg/ml. Occidiofungin retains its in vitro potency in the presence of 5% and 50% human serum with a minimal lethal concentration (MLC) of 2 and 4 µg/ml, respectively. Time-kill and postantifungal effect (PAFE) experiments of occidiofungin against Candida albicans were performed. The results demonstrate that occidiofungin is fungicidal. Occidiofungin was also found to be a very stable molecule. It is resistant to extreme temperatures and pH and maintains its activity following exposure to gastric proteases.

Adverse Endocrine-Related Effects of Pembrolizumab Precipitating Severe Hyponatremia.

Pembrolizumab is an immune-checkpoint inhibitor (ICI), designed as a highly selective anti-programmed death-1 (PD-1) humanized monoclonal antibody, which ultimately inhibits the negative immune regulation due to PD-1 receptor signaling. This inhibition allows for anti-tumor response and reverses T cell suppression. We present a case report of a 53-year-old woman who was treated with pembrolizumab for metastatic melanoma. There have been adverse endocrine-related effects of pembrolizumab, as well as other ICI medications, including hypothyroidism and secondary adrenal insufficiency. Adrenal insufficiency and hypothyroidism can precipitate hyponatremia through different mechanisms. We report a case of a patient developing severe hyponatremia likely precipitated by endocrine-related side effects of pembrolizumab.