Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound.

Détails

ID Serval
serval:BIB_C07763C7CB83
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound.
Périodique
Journal of medicinal chemistry
Auteur(s)
Deodato D., Maccari G., De Luca F., Sanfilippo S., Casian A., Martini R., D'Arezzo S., Bonchi C., Bugli F., Posteraro B., Vandeputte P., Sanglard D., Docquier J.D., Sanguinetti M., Visca P., Botta M.
ISSN
1520-4804 (Electronic)
ISSN-L
0022-2623
Statut éditorial
Publié
Date de publication
28/04/2016
Peer-reviewed
Oui
Volume
59
Numéro
8
Pages
3854-3866
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
We recently identified a novel family of macrocyclic amidinoureas showing potent antifungal activity against Candida spp. In this study, we demonstrate the fungicidal effect of these compounds as well as their killing activity in a dose-dependent manner. Transcriptional analysis data indicate that our molecules induce a significant change in the transcriptome involving ATP binding cassette (ABC) transporter genes. Notably, experiments against Candida albicans mutants lacking those genes showed resistance to the compound, suggesting the involvement of ABC transporters in the uptake or intracellular accumulation of the molecule. To probe the mode of action, we performed fluorescence microscopy experiments on fungal cells treated with an ad-hoc synthesized fluorescent derivative. Fluorescence microscopy images confirm the ability of the compound to cross the membrane and show a consistent accumulation within the cytoplasm. Finally, we provide data supporting the in vivo efficacy in a systemic infection murine model setup with a drug-resistant strain of C. albicans.

Mots-clé
Animals, Antifungal Agents/chemistry, Antifungal Agents/pharmacology, Colony Count, Microbial, Macrocyclic Compounds/chemistry, Macrocyclic Compounds/pharmacology, Mice, Microbial Sensitivity Tests, Microscopy, Fluorescence, Yeasts/drug effects, Yeasts/isolation & purification
Pubmed
Web of science
Création de la notice
28/05/2016 10:21
Dernière modification de la notice
03/03/2018 21:05
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