Article (Scientific journals)
Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound
Deodato, D.; Maccari, G.; De Luca, F. et al.
2016In Journal of Medicinal Chemistry, 59 (8), p. 3854-3866
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Keywords :
ABC transporter; ABC transporter gene; Article; Candida albicans; Animals; Antifungal Agents; Colony Count, Microbial; Macrocyclic Compounds; Mice; Microbial Sensitivity Tests; Microscopy, Fluorescence; Yeasts
Abstract :
[en] 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. © 2016 American Chemical Society.
Disciplines :
Life sciences: Multidisciplinary, general & others
Microbiology
Author, co-author :
Deodato, D.;  Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy, Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, Castelnuovo Berardenga, I-53019, Italy
Maccari, G.;  Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy, Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, Castelnuovo Berardenga, I-53019, Italy
De Luca, F.;  Department of Medical Biotechnology, University of Siena, Siena, I-53100, Italy
Sanfilippo, S.;  Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
Casian, A.;  Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
Martini, R.;  Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy
D'Arezzo, S.;  Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, Roma, I-00149, Italy
Bonchi, C.;  Dipartimento di Scienze, Università Roma Tre, Roma, I-00154, Italy
Bugli, F.;  Institute of Microbiology, Università Cattolica Del Sacro Cuore, Roma, I-00168, Italy
Posteraro, B.;  Institute of Public Health, Università Cattolica Del Sacro Cuore, Roma, I-00168, Italy
Vandeputte, P.;  Institute of Microbiology, University of Lausanne, University Hospital Center, Lausanne, CH-1011, Switzerland
Sanglard, D.;  Institute of Microbiology, University of Lausanne, University Hospital Center, Lausanne, CH-1011, Switzerland
Docquier, Jean-Denis ;  Université de Liège - ULiège > Département des sciences de la vie > Centre d'ingénierie des protéines
Sanguinetti, M.;  Institute of Microbiology, Università Cattolica Del Sacro Cuore, Roma, I-00168, Italy, Institute of Public Health, Università Cattolica Del Sacro Cuore, Roma, I-00168, Italy
Visca, P.;  Dipartimento di Scienze, Università Roma Tre, Roma, I-00154, Italy
Botta, M.;  Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, I-53100, Italy, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, BioLife Science Building, 1900 North 12th Street, Philadelphia, PA 19122, United States, Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, Castelnuovo Berardenga, I-53019, Italy
More authors (6 more) Less
Language :
English
Title :
Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound
Publication date :
2016
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society
Volume :
59
Issue :
8
Pages :
3854-3866
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 19 November 2020

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