Back to Search
Start Over
A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity
- Source :
- PLoS ONE, Ronco, T, Aragao, F M, Saaby, L, Christensen, J B, Permin, A, Williams, A R, Thamsborg, S M & Olsen, R H 2021, ' A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity ', PLoS ONE, vol. 16, no. 10, e0258207 . https://doi.org/10.1371/journal.pone.0258207, PLoS ONE, Vol 16, Iss 10, p e0258207 (2021)
- Publication Year :
- 2021
- Publisher :
- Public Library of Science, 2021.
-
Abstract
- 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.
- Subjects :
- Cell Lines
Cytotoxicity
Administration, Oral
Artificial Gene Amplification and Extension
Thioridazine
Pharmacology
Pathology and Laboratory Medicine
Toxicology
Polymerase Chain Reaction
chemistry.chemical_compound
Feces
Mice
Oral administration
Phenothiazines
RNA, Ribosomal, 16S
Medicine and Health Sciences
Multidisciplinary
Chemistry
Antimicrobials
Drugs
Antimicrobial
Bacterial Pathogens
Medical Microbiology
Toxicity
Medicine
Biological Cultures
Anatomy
Pathogens
medicine.drug
Research Article
Clostridium Difficile
Science
Cmax
Research and Analysis Methods
Microbiology
Antibiotic resistance
Phenothiazine
Microbial Control
medicine
Animals
Humans
Molecular Biology Techniques
Molecular Biology
Microbial Pathogens
Minimum bactericidal concentration
Bacteria
Clostridioides difficile
Gut Bacteria
Organisms
Biology and Life Sciences
Gastrointestinal Microbiome
Gastrointestinal Tract
Clostridium Infections
Caco-2 Cells
Digestive System
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 16
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....82b39e055eb25e967ae3412b444f1a89