New Inhibitors of Chorismate Synthase Present Antifungal Activity Against <i>Paracoccidioides Brasiliensis</i>

Abstract

<b>Aim:</b> A structural model of chorismate synthase (CS) from the pathogenic fungus <i>Candida albicans</i> was used for virtual screening simulations. <b>Methods:</b> Docking, molecular dynamics, cell growth inhibition and protein binding assays were used for search and validation. <b>Results:</b> Two molecules termed CS8 and CaCS02 were identified. Further studies of the minimal inhibitory concentration demonstrated fungicidal activity against <i>Paracoccidioides brasiliensis</i> with a minimal inhibitory concentration and minimal fungicidal concentration of 512 and 32 μg·ml^-1 for CS8 and CaCS02, respectively. In addition, CaCS02 showed a strong synergistic effect in combination with amphotericin B without cytotoxic effects. <i>In vitro</i> studies using recombinant CS from <i>P. brasiliensis</i> showed IC₅₀ of 29 μM for CaCS02 supporting our interpretation that inhibition of CS causes the observed fungicidal activity.