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Tytuł:
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In vitro characterization, ADME analysis, and histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains.
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Autorzy:
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Orofino F; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
Truglio GI; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
Fiorucci D; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
D'Agostino I; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
Borgini M; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
Poggialini F; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
Zamperini C; Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.
Dreassi E; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
Maccari L; Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.
Torelli R; Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Dipartimento di Scienze di Laboratorio e Infettivologiche, Rome, Italy.
Martini C; Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy.
Bernabei M; Istituto di Anatomia Patologica, Fondazione Policlinico Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
Meis JF; Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands; Radboud University Medical Center, Nijmegen, the Netherlands.
Khandelwal NK; School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Prasad R; Amity Institute of Integrative Sciences and Health, Amity University, Gurgaon 122413, Haryana, India.
Sanguinetti M; Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Dipartimento di Scienze di Laboratorio e Infettivologiche, Rome, Italy; Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy.
Bugli F; Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Dipartimento di Scienze di Laboratorio e Infettivologiche, Rome, Italy; Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address: .
Botta M; 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; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Philadelphia, PA 19122, USA.
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Źródło:
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International journal of antimicrobial agents [Int J Antimicrob Agents] 2020 Mar; Vol. 55 (3), pp. 105865. Date of Electronic Publication: 2019 Dec 20.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: Amsterdam : Elsevier Science Publishers, c1991-
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MeSH Terms:
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Antifungal Agents/*pharmacology
Candida/*drug effects
Guanidine/*analogs & derivatives
Urea/*analogs & derivatives
Animals ; Antifungal Agents/therapeutic use ; Azoles/pharmacology ; Candidiasis/drug therapy ; Drug Resistance, Fungal/drug effects ; Guanidine/pharmacology ; Guanidine/therapeutic use ; Microbial Sensitivity Tests ; Rats ; Urea/pharmacology ; Urea/therapeutic use
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Contributed Indexing:
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Keywords: ADME; Candida; antifungal; in vitro; in vivo; pharmacokinetics
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Substance Nomenclature:
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0 (Antifungal Agents)
0 (Azoles)
141-83-3 (guanidine carboxamide)
8W8T17847W (Urea)
JU58VJ6Y3B (Guanidine)
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Entry Date(s):
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Date Created: 20191224 Date Completed: 20200325 Latest Revision: 20200325
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Update Code:
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20240105
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DOI:
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10.1016/j.ijantimicag.2019.105865
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PMID:
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31866465
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Background: Candida species are one of the most common causes of nosocomial bloodstream infections among the opportunistic fungi. Extensive use of antifungal agents, most of which were launched on the market more than 20 years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. We recently described a novel class of antifungal macrocyclic compounds with an amidinourea moiety that is highly active against azole-resistant Candida strains.
Objective: A compound from this family, BM1, was investigated in terms of in vitro activity against various Candida species, including C. auris isolates, interaction with the ABC transporter, CDR6, and in vivo distribution and safety.
Methods: In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) were used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis were utilised to evaluate in vivo toxicology, pharmacokinetics, and distribution.
Results: The current research shows BM1 has a low in vivo toxicity profile, affinity for the renal system in rats, and good absorption, distribution, metabolism, and excretion (ADME). BM1 also has potent activity against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains.
Conclusions: The results confirmed low minimum inhibitory concentrations (MICs) against several Candida species, including preliminary data vs. C. auris. BM1 has good ADME and biochemical characteristics, is suitable and safe for daily administration and is particularly indicated for renal infections. These data indicate BM1 and its derivatives form a novel, promising antifungal class.
(Copyright © 2020. Published by Elsevier B.V.)
