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

Author(s)
Davide Deodato, Giorgio Maccari, Filomena De Luca, Stefania Sanfilippo, Alexandru Casian, Riccardo Martini, Silvia D'Arezzo, Carlo Bonchi, Francesca Bugli, Brunella Posteraro, Patrick Vandeputte, Dominique Sanglard, Jean-Denis Docquier, Maurizio Sanguinetti, Paolo Visca, Maurizio Botta
Abstract

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.

Organisation(s)
Department of Pharmaceutical Chemistry, Department of Microbiology, Immunobiology and Genetics
Journal
Journal of Medicinal Chemistry
Volume
59
Pages
3854-66
No. of pages
13
ISSN
0022-2623
DOI
https://doi.org/10.1021/acs.jmedchem.6b00018
Publication date
04-2016
Publication status
Published
Peer reviewed
Yes
Austrian Fields of Science 2012
301207 Pharmaceutical chemistry
Keywords
Animals, Antifungal Agents/chemistry, Colony Count, Microbial, Macrocyclic Compounds/chemistry, Mice, Microbial Sensitivity Tests, Microscopy, Fluorescence, Yeasts/drug effects
Portal url
https://ucris.univie.ac.at/portal/en/publications/biological-characterization-and-in-vivo-assessment-of-the-activity-of-a-new-synthetic-macrocyclic-antifungal-compound(364f22f4-3e06-436b-8617-11c566e7fc69).html