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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3854-3866
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number8
DOIs
Publication statusPublished - Apr 28 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    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. (2016). Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound. Journal of Medicinal Chemistry, 59(8), 3854-3866. https://doi.org/10.1021/acs.jmedchem.6b00018