Localizing Antifungal Drugs to the Correct Organelle Can Markedly Enhance their Efficacy

Abstract

A critical aspect of drug design is 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. This study demonstrates, as a proof of principle, that drug efficacy can be increased considerably by a structural modification that targets it to the relevant organelle. Specifically, by varying the fluorescent dye segment an antifungal azole was directed from the fungal cell mitochondria to the endoplasmic reticulum (ER), the organelle that harbors the drug target. The ER-localized azole displayed up to two orders of magnitude improved antifungal activity and also dramatically reduced the growth of drug-tolerant fungal subpopulations in a panel of Candida species, which are the most prevalent causes of serious human fungal infections. The principle underlying the "target organelle localization" approach provides a new paradigm to improve drug potency and replenish the limited pipeline of antifungal drugs.

Cationic Amphiphiles Induce Macromolecule Denaturation and Organelle Decomposition in Pathogenic Yeast

“…The incidence of fungal infections has risen sharply in recent decades and the prevention and treatment of these infections relies on a very limited number of classes of antifungal drugs . Therefore, in recent years, several research groups, including ours, have been engaged in the study and development of membrane‐disrupting antifungal cationic amphiphiles based on the pseudo‐oligosaccharide structures of aminoglycoside (AG) antibiotics .…”

Cationic Amphiphiles Induce Macromolecule Denaturation and Organelle Decomposition in Pathogenic Yeast

“…[7][8][9] Thei ncidence of fungal infections has risen sharply in recent decades and the prevention and treatment of these infections relies on av ery limited number of classes of antifungal drugs. [10][11][12] Therefore,i nr ecent years,s everal research groups,i ncluding ours,h ave been engaged in the study and development of membrane-disrupting antifungal cationic amphiphiles based on the pseudo-oligosaccharide structures of aminoglycoside (AG) antibiotics. [13][14][15][16][17][18] The design of these antifungal agents is based on the attachment of hydrophobic residues to one or more positions of the AG scaffold.…”

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

“…[76] Themore hydrophilic naphthalimide-derived probes localized to lysosomes,a nd the more hydrophobic naphthalimide derivatives localized to the ER with high selectivity.W er ecently demonstrated that implementing the organelle-targeting approach can improve the performance of azole antifungal drugs. [77] Members of the azole class of antifungal drugs are the first-line treatment for invasive fungal infections. [78][79][80] Despite three decades of broad clinical use,fundamental questions about the uptake and localization of antifungal azoles within fungal cells had remained unanswered.…”