Novel keto-alkyl-pyridinium antifungal molecules active in models of in vivoCandida albicansvascular catheter infection and ex vivoCandida aurisskin colonization

Abstract

AbstractNew antifungal therapies are needed for both systemic, invasive infections as well as superficial infections of mucosal and skin surfaces as well as biofilms associated with medical devices. The resistance of biofilm and biofilm-like growth phases of fungi contributes to the poor efficacy of systemic therapies to non-systemic infections. Here, we describe the identification and characterization of a novel keto-alkyl-pyridinium scaffold with broad spectrum activity (2-16 µg/mL) against medically important yeasts and moulds, including clinical isolates resistant to azoles and/or echinocandins. Furthermore, these keto-alkyl-pyridinium agents retain substantial activity against biofilm phase yeast and have direct activity against hyphalA. fumigatus. Although their toxicity precludes use in systemic infections, we found that the keto-alkyl-pyridinium molecules reduceC. albicansfungal burden in a rat model of vascular catheter infection and reduceCandida auriscolonization in a porcine ex vivo model. These initial pre-clinical data suggest that molecules of this class may warrant further study and development.