Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans.
autophagy
candida albicans
ergosterol plasma membrane localization
otilonium bromide
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
12 Jul 2024
12 Jul 2024
Historique:
received:
11
06
2024
medline:
12
7
2024
pubmed:
12
7
2024
entrez:
12
7
2024
Statut:
aheadofprint
Résumé
Candidiasis, which presents a substantial risk to human well-being, is frequently treated with azoles. However, drug-drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)-approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle-mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole-mediated liver enzyme inhibition and avoids export-mediated drug resistance in C. albicans.
Identifiants
pubmed: 38995235
doi: 10.1002/advs.202406473
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2406473Subventions
Organisme : National Key Research and Development Program of China
ID : 2022YFC2303004
Organisme : National Key Research and Development Program of China
ID : 2021YFC2300404
Organisme : National Natural Science Foundation of China
ID : 82020108032
Organisme : Innovation Program of Shanghai Municipal Education Commission
ID : 202101070007-E00094
Informations de copyright
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.
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