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

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 ABC transporters 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 Candida albicans.
Original languageEnglish
Pages (from-to)N/A-N/A
JournalJournal of Medicinal Chemistry
DOIs
Publication statusPublished - 2016

Keywords

  • Candida albicans

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