Effects of novel organoantimony compounds on the fungal pathogen Cryptococcus neoformans

<b>Introduction.</b> <i>Cryptococcus neoformans</i> is an opportunistic fungal pathogen that causes pulmonary cryptococcosis, or an acute or chronic infection in the lungs, and cryptococcal meningitis, an infection of the brain and spinal column, in immunocompromised individuals. Fungal infections are responsible for ~1.7 million deaths each year. In contrast to antibacterial drugs, the quantity of antifungal drugs capable of combating fungal infections remains low. With high toxicity and increased resistance to antifungals in recent years, the importance of finding new options for antifungal therapy is even more crucial.<b>Hypothesis.</b> We hypothesized that a series of organoantimony compounds that previously exhibited antifungal activity could serve as effective antifungal drugs.<b>Aim.</b> We aimed to evaluate the antifungal activity of these compounds and their mechanism of action.<b>Methodology.</b> We first evaluated antifungal activity via MIC and minimum fungicidal concentration assay. Next, we evaluated cytotoxicity, followed by mechanistic studies via electron microscopy and RNA sequencing studies. Finally, we evaluated activity <i>in vivo</i> using a <i>Galleria mellonella</i> model.<b>Results.</b> Results showed that several compounds were antifungal and also non-toxic. RNA sequencing identified several differentially regulated <i>C. neoformans</i> genes and pathways, including those associated with membrane transport and formation, ribosome biogenesis and gene expression. Scanning electron microscopy and transmission electron microscopy studies show altered morphology and cellular death following the treatment of <i>C. neoformans</i> with the compounds. Compounds had moderate efficacy in the <i>G. mellonella</i> infection model.<b>Conclusion.</b> These studies show that organoantimony compounds are promising antifungal therapies, and more studies are currently underway to improve efficacy and narrow down their mechanism(s) of antifungal activity.