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Background Invasive candidiasis is a growing health threat. In the last five years, the WHO has prioritized fungal pathogens, and the CDC has reported a more than 80% increase in nosocomial Candida infections. With resistance to first-line antimycotics also rising, new treatment and prophylactic measures are needed. Glycogen synthase kinase (GSK) is a potential target for fungal pathogens. Some GSK inhibitors have passed Phase 1 clinical trials for indications like bipolar disorder and Alzheimer’s disease. If the safety profiles of potential fungal medication are favorable, or if a potential medication has selectivity for fungal homologs of GSK, fungal GSK could be a novel drug target. Not much is known about the moonlighting functions of Candida GSK. This work screens GSK inhibitors against Candida to examine cell growth inhibition.
Methods Candida parapsilosis (ATCC 22019) was grown planktonically in YM broth, containing penicillin and streptomycin, at 33°C. GSK inhibitors were purchased from AOBIOUS (Gloucester, MA) and dissolved in DSMO, with a final culture concentration of 0.5% DMSO. Inhibitor screens were run in triplicate in a clear, flat-bottom 96-well plate, and growth/inhibition was monitored by OD600. Glycogen content in cell cultures was monitored by absorbance at 660 nm after iodine/potassium iodide stain.
Results Several GSK inhibitors, including tideglusib, were found to slow or block Candida growth at micromolar concentrations. Some GSK inhibitors had activities comparable to known antifungal agents tested. GSK inhibitors tested encompassed diversity in molecular structure, though some molecules like tideglusib and TDZD-8 shared pharmacophores. Besides inhibiting growth, treatment of GSK inhibitors at sub-MIC concentrations resulted in lower glycogen content.
Conclusion Our results indicate growth inhibition of Candida with GSK inhibitors. This work is foundation chemical biology studies to elucidate moonlighting functions of fungal GSK. Next steps will be to perform synergy screens to test if the GSK inhibitors increase or decrease bioactivity of known antifungals, and vice versa. Future directions also include pursuing cloning of Candida GSK for biochemical screens of the active compounds.
