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

Raphael I. Benhamou, Maayan Bibi, Judith Berman, Micha Fridman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageAmerican English
Pages (from-to)6230-6235
Number of pages6
JournalAngewandte Chemie - International Edition
Volume57
Issue number21
DOIs
StatePublished - 22 May 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • Candida
  • antifungal agents
  • azole drugs
  • fluorogenic probes
  • organelle-targeting drugs

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