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.
authors.affiliation: Department of Biotechnology Chemistry and Pharmacy, University of Siena , I-53100 Siena, Italy.|Lead Discovery Siena s.r.l. , Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Deodato
authors.affiliation: Department of Biotechnology Chemistry and Pharmacy, University of Siena , I-53100 Siena, Italy.|Lead Discovery Siena s.r.l. , Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Maccari
authors.affiliation: Department of Medical Biotechnology, University of Siena , I-53100 Siena, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: De Luca
authors.affiliation: Department of Biotechnology Chemistry and Pharmacy, University of Siena , I-53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sanfilippo
authors.affiliation: Department of Biotechnology Chemistry and Pharmacy, University of Siena , I-53100 Siena, Italy.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Casian
authors.affiliation: Department of Biotechnology Chemistry and Pharmacy, University of Siena , I-53100 Siena, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Martini
authors.affiliation: Istituto Nazionale per le Malattie Infettive "Lazzaro Spallanzani" , I-00149 Roma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Arezzo
authors.affiliation: Dipartimento di Scienze, Università Roma Tre , I-00154 Roma, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Bonchi
authors.affiliation: Institute of Microbiology, Università Cattolica del Sacro Cuore , I-00168 Roma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bugli
authors.affiliation: Institute of Public Health, Università Cattolica del Sacro Cuore , I-00168 Roma, Italy.
authors.forename: Brunella
authors.initials: B
authors.lastname: Posteraro
authors.affiliation: Institute of Microbiology, University of Lausanne and University Hospital Center , CH-1011 Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vandeputte
authors.affiliation: Institute of Microbiology, University of Lausanne and University Hospital Center , CH-1011 Lausanne, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
authors.affiliation: Department of Medical Biotechnology, University of Siena , I-53100 Siena, Italy.|Lead Discovery Siena s.r.l. , Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Docquier
authors.affiliation: Institute of Microbiology, Università Cattolica del Sacro Cuore , I-00168 Roma, Italy.|Institute of Public Health, Università Cattolica del Sacro Cuore , I-00168 Roma, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.affiliation: Dipartimento di Scienze, Università Roma Tre , I-00154 Roma, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Visca
authors.affiliation: Department of Biotechnology Chemistry and Pharmacy, University of Siena , I-53100 Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Temple University , BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, Pennsylvania 19122, United States .|Lead Discovery Siena s.r.l. , Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D015169:Colony Count, Microbial; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D008856:Microscopy, Fluorescence; D015003:Yeasts / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000935:Antifungal Agents; D047028:Macrocyclic Compounds