Indirect Disruption of Pathogenic Fungal Membrane by Organelle-targeted Antifungal Azoles

One of the most important questions in the process of drug design is how to achieve optimal target inhibition by specifically delivering the drug molecule not only to the target tissue or cell but also to its therapeutically active site within the cell. We recently established that chemical modification can alter the subcellular distribution of antifungal azole drugs from the fungal mitochondria to the endoplasmic reticulum (ER). The ER harbors the ergosterol biosynthesis pathway, including the cytochrome P-450-dependent lanosterol demethylase that is the drug target. The ER-localized azole displayed markedly improved antifungal activity and dramatically reduced the growth of drug-tolerant fungal subpopulations in a broad panel of Candida species, which are the most prevalent causes of serious human fungal infections. Modulation of the subcellular distribution did not change the mode of action of the antifungal azole. Moreover, despite the significant improvement in antifungal potency, the low toxicity of the ER-directed azole was comparable to that of the widely used antifungal azole drug fluconazole. The principle underlying the “target-organelle directed drug” (TODD) approach confers an important improvement to the efficacy of antifungal azoles and, more generally, provides a new paradigm for the improvement of drug potency that is needed to replenish the very limited pipeline of antifungal drug candidates.