Something Old Brings New Insights: Activity of Cerivastatin Against Thermally Dimorphic Fungi and Its Potential as an Antifungal Scaffold

<b>Background/Objectives</b>: Species of the <i>Sporothrix</i> genus were used as a biological model to identify potential antifungal compounds within the NIH Clinical Collection library. <b>Methods</b>: A total of 707 compounds were screened for antifungal activity using in vitro susceptibility assays. Compounds exhibiting significant inhibitory effects (growth inhibitions greater than 80%) were further evaluated by determining their minimum inhibitory concentrations (MICs). As cerivastatin demonstrated the highest activity after itraconazole, it was selected for further evaluation, either alone or in combination with itraconazole, using susceptibility assays, electron microscopy, and flow cytometry analyses. <b>Results</b>: Among the screened compounds, twenty-six showed significant inhibition of yeast growth (≥80%). Compounds with previously reported antifungal activity or not used as oral treatment were excluded from further analysis. MIC determination of eleven selected compounds revealed that cerivastatin inhibited the growth of <i>Sporothrix brasiliensis</i>, <i>Sporothrix schenckii</i>, and <i>Sporothrix globosa</i> at concentrations of 1.25 µM and 0.6 µM. Combination treatment with cerivastatin and itraconazole resulted in greater inhibition of <i>Sporothrix</i> growth than either agent alone. Flow cytometry and microscopic analyses revealed more pronounced morphophysiological alterations in yeast cells following combination treatment. <b>Conclusions</b>: These findings highlight the potential of cerivastatin as an antifungal agent when used in combination with itraconazole. Furthermore, the chemical scaffold of cerivastatin warrants further investigation as a basis for the development of novel statins with antifungal activity.