A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.

The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are matters of concern for public health. Thioridazine, a compound belonging to the phenothiazine group, has previous shown antimicrobial...

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Autores principales: Troels Ronco, Francisca Maria Aragao, Lasse Saaby, Jørn B Christensen, Anders Permin, Andrew R Williams, Stig M Thamsborg, Rikke H Olsen
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Publicado: Public Library of Science (PLoS) 2021
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spelling oai:doaj.org-article:6ea30fd443644510893431c84e425e632021-12-02T20:17:23ZA new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.1932-620310.1371/journal.pone.0258207https://doaj.org/article/6ea30fd443644510893431c84e425e632021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0258207https://doaj.org/toc/1932-6203The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are matters of concern for public health. Thioridazine, a compound belonging to the phenothiazine group, has previous shown antimicrobial activity against C. difficile. The purpose of this present study was to investigate the potential of a novel phenothiazine derivative, JBC 1847, as an oral antimicrobial for treatment of intestinal pathogens and CDIs. The minimal inhibition concentration and the minimum bactericidal concentration of JBC 1847 against C. difficile ATCC 43255 were determined 4 μg/mL and high tolerance after oral administration in mice was observed (up to 100 mg/kg bodyweight). Pharmacokinetic modeling was conducted in silico using GastroPlusTM, predicting low (< 10%) systemic uptake after oral exposure and corresponding low Cmax in plasma. Impact on the intestinal bacterial composition after four days of treatment was determined by 16s rRNA MiSeq sequencing and revealed only minor impact on the microbiota in non-clinically affected mice, and there was no difference between colony-forming unit (CFU)/gram fecal material between JBC 1847 and placebo treated mice. The cytotoxicity of the compound was assessed in Caco-2 cell-line assays, in which indication of toxicity was not observed in concentrations up to seven times the minimal bactericidal concentration. In conclusion, the novel phenothiazine derivative demonstrated high antimicrobial activity against C. difficile, had low predicted gastrointestinal absorption, low intestinal (in vitro) cytotoxicity, and only induced minor changes of the healthy microbiota, altogether supporting that JBC 1847 could represent a novel antimicrobial candidate. The clinical importance hereof calls for future experimental studies in CDI models.Troels RoncoFrancisca Maria AragaoLasse SaabyJørn B ChristensenAnders PerminAndrew R WilliamsStig M ThamsborgRikke H OlsenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10, p e0258207 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Troels Ronco
Francisca Maria Aragao
Lasse Saaby
Jørn B Christensen
Anders Permin
Andrew R Williams
Stig M Thamsborg
Rikke H Olsen
A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.
description The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are matters of concern for public health. Thioridazine, a compound belonging to the phenothiazine group, has previous shown antimicrobial activity against C. difficile. The purpose of this present study was to investigate the potential of a novel phenothiazine derivative, JBC 1847, as an oral antimicrobial for treatment of intestinal pathogens and CDIs. The minimal inhibition concentration and the minimum bactericidal concentration of JBC 1847 against C. difficile ATCC 43255 were determined 4 μg/mL and high tolerance after oral administration in mice was observed (up to 100 mg/kg bodyweight). Pharmacokinetic modeling was conducted in silico using GastroPlusTM, predicting low (< 10%) systemic uptake after oral exposure and corresponding low Cmax in plasma. Impact on the intestinal bacterial composition after four days of treatment was determined by 16s rRNA MiSeq sequencing and revealed only minor impact on the microbiota in non-clinically affected mice, and there was no difference between colony-forming unit (CFU)/gram fecal material between JBC 1847 and placebo treated mice. The cytotoxicity of the compound was assessed in Caco-2 cell-line assays, in which indication of toxicity was not observed in concentrations up to seven times the minimal bactericidal concentration. In conclusion, the novel phenothiazine derivative demonstrated high antimicrobial activity against C. difficile, had low predicted gastrointestinal absorption, low intestinal (in vitro) cytotoxicity, and only induced minor changes of the healthy microbiota, altogether supporting that JBC 1847 could represent a novel antimicrobial candidate. The clinical importance hereof calls for future experimental studies in CDI models.
format article
author Troels Ronco
Francisca Maria Aragao
Lasse Saaby
Jørn B Christensen
Anders Permin
Andrew R Williams
Stig M Thamsborg
Rikke H Olsen
author_facet Troels Ronco
Francisca Maria Aragao
Lasse Saaby
Jørn B Christensen
Anders Permin
Andrew R Williams
Stig M Thamsborg
Rikke H Olsen
author_sort Troels Ronco
title A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.
title_short A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.
title_full A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.
title_fullStr A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.
title_full_unstemmed A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.
title_sort new phenothiazine derivate is active against clostridioides difficile and shows low cytotoxicity.
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/6ea30fd443644510893431c84e425e63
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