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

7 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 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

Fingerprint

Macrocyclic Compounds
ATP-Binding Cassette Transporters
Candida albicans
Fluorescence Microscopy
Transcriptome
Candida
Genes
Cytoplasm
Membranes
Infection
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound. / Deodato, Davide; Maccari, Giorgio; De Luca, Filomena; Sanfilippo, Stefania; Casian, Alexandru; Martini, Riccardo; D'Arezzo, Silvia; Bonchi, Carlo; Bugli, Francesca; Posteraro, Brunella; Vandeputte, Patrick; Sanglard, Dominique; Docquier, Jean Denis; Sanguinetti, Maurizio; Visca, Paolo; Botta, Maurizio.

In: Journal of Medicinal Chemistry, Vol. 59, No. 8, 28.04.2016, p. 3854-3866.

Research output: Contribution to journalArticle

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, JD, 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, vol. 59, no. 8, pp. 3854-3866. https://doi.org/10.1021/acs.jmedchem.6b00018
Deodato, Davide ; Maccari, Giorgio ; De Luca, Filomena ; Sanfilippo, Stefania ; Casian, Alexandru ; Martini, Riccardo ; D'Arezzo, Silvia ; Bonchi, Carlo ; Bugli, Francesca ; Posteraro, Brunella ; Vandeputte, Patrick ; Sanglard, Dominique ; Docquier, Jean Denis ; Sanguinetti, Maurizio ; Visca, Paolo ; Botta, Maurizio. / Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 8. pp. 3854-3866.
@article{bbb25d0892714730b2f2c5b4c083f8d2,
title = "Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound",
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.",
author = "Davide Deodato and Giorgio Maccari and {De Luca}, Filomena and Stefania Sanfilippo and Alexandru Casian and Riccardo Martini and Silvia D'Arezzo and Carlo Bonchi and Francesca Bugli and Brunella Posteraro and Patrick Vandeputte and Dominique Sanglard and Docquier, {Jean Denis} and Maurizio Sanguinetti and Paolo Visca and Maurizio Botta",
year = "2016",
month = "4",
day = "28",
doi = "10.1021/acs.jmedchem.6b00018",
language = "English",
volume = "59",
pages = "3854--3866",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound

AU - Deodato, Davide

AU - Maccari, Giorgio

AU - De Luca, Filomena

AU - Sanfilippo, Stefania

AU - Casian, Alexandru

AU - Martini, Riccardo

AU - D'Arezzo, Silvia

AU - Bonchi, Carlo

AU - Bugli, Francesca

AU - Posteraro, Brunella

AU - Vandeputte, Patrick

AU - Sanglard, Dominique

AU - Docquier, Jean Denis

AU - Sanguinetti, Maurizio

AU - Visca, Paolo

AU - Botta, Maurizio

PY - 2016/4/28

Y1 - 2016/4/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84968832503&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84968832503&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.6b00018

DO - 10.1021/acs.jmedchem.6b00018

M3 - Article

VL - 59

SP - 3854

EP - 3866

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -