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A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens
Thioridazine hydrochloride (HCl) has been suggested as a promising antimicrobial helper compound for the treatment of infections with antimicrobial-resistant bacteria. Unfortunately, the therapeutic concentration of thioridazine HCl is generally higher than what can be tolerated clinically, in part...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344759/ https://www.ncbi.nlm.nih.gov/pubmed/32549350 http://dx.doi.org/10.3390/antibiotics9060327 |
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author | Jørgensen, Nadia S. Saaby, Lasse Andersson, Anne M. Kromann, Sofie Sheikhsamani, Ehsan Permin, Anders Ronco, Troels Svenningsen, Søren W. Christensen, Jørn B. Olsen, Rikke H. |
author_facet | Jørgensen, Nadia S. Saaby, Lasse Andersson, Anne M. Kromann, Sofie Sheikhsamani, Ehsan Permin, Anders Ronco, Troels Svenningsen, Søren W. Christensen, Jørn B. Olsen, Rikke H. |
author_sort | Jørgensen, Nadia S. |
collection | PubMed |
description | Thioridazine hydrochloride (HCl) has been suggested as a promising antimicrobial helper compound for the treatment of infections with antimicrobial-resistant bacteria. Unfortunately, the therapeutic concentration of thioridazine HCl is generally higher than what can be tolerated clinically, in part due to its toxic side effects on the central nervous system. Therefore, we aimed to synthesize a less toxic thioridazine derivative that would still retain its properties as a helper compound. This resulted in a compound designated 1-methyl-2-(2-(2-(methylthio)-10H-phenothiazin-10-yl)ethyl)-1-pentylpiperidin-1-ium bromide (abbreviated T5), which exhibited low blood–brain barrier permeability. The lowest minimal inhibitory concentration (MIC) against Staphylococcus aureus exposed to the novel compound was reduced 32-fold compared to thioridazine HCl (from 32 µg/mL to 1 µg/mL). The MIC values for T5 against five Gram-positive pathogens ranged from 1 µg/mL to 8 µg/mL. In contrast to thioridazine HCl, T5 does not act synergistically with oxacillin. In silico predictive structure analysis of T5 suggests that an acceptably low toxicity and lack of induced cytotoxicity was demonstrated by a lactate dehydrogenase assay. Conclusively, T5 is suggested as a novel antimicrobial agent against Gram-positive bacteria. However, future pharmacokinetic and pharmacodynamic studies are needed to clarify the clinical potential of this novel discovery. |
format | Online Article Text |
id | pubmed-7344759 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73447592020-07-09 A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens Jørgensen, Nadia S. Saaby, Lasse Andersson, Anne M. Kromann, Sofie Sheikhsamani, Ehsan Permin, Anders Ronco, Troels Svenningsen, Søren W. Christensen, Jørn B. Olsen, Rikke H. Antibiotics (Basel) Article Thioridazine hydrochloride (HCl) has been suggested as a promising antimicrobial helper compound for the treatment of infections with antimicrobial-resistant bacteria. Unfortunately, the therapeutic concentration of thioridazine HCl is generally higher than what can be tolerated clinically, in part due to its toxic side effects on the central nervous system. Therefore, we aimed to synthesize a less toxic thioridazine derivative that would still retain its properties as a helper compound. This resulted in a compound designated 1-methyl-2-(2-(2-(methylthio)-10H-phenothiazin-10-yl)ethyl)-1-pentylpiperidin-1-ium bromide (abbreviated T5), which exhibited low blood–brain barrier permeability. The lowest minimal inhibitory concentration (MIC) against Staphylococcus aureus exposed to the novel compound was reduced 32-fold compared to thioridazine HCl (from 32 µg/mL to 1 µg/mL). The MIC values for T5 against five Gram-positive pathogens ranged from 1 µg/mL to 8 µg/mL. In contrast to thioridazine HCl, T5 does not act synergistically with oxacillin. In silico predictive structure analysis of T5 suggests that an acceptably low toxicity and lack of induced cytotoxicity was demonstrated by a lactate dehydrogenase assay. Conclusively, T5 is suggested as a novel antimicrobial agent against Gram-positive bacteria. However, future pharmacokinetic and pharmacodynamic studies are needed to clarify the clinical potential of this novel discovery. MDPI 2020-06-15 /pmc/articles/PMC7344759/ /pubmed/32549350 http://dx.doi.org/10.3390/antibiotics9060327 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Jørgensen, Nadia S. Saaby, Lasse Andersson, Anne M. Kromann, Sofie Sheikhsamani, Ehsan Permin, Anders Ronco, Troels Svenningsen, Søren W. Christensen, Jørn B. Olsen, Rikke H. A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens |
title | A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens |
title_full | A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens |
title_fullStr | A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens |
title_full_unstemmed | A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens |
title_short | A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens |
title_sort | novel derivative of thioridazine shows low toxicity and efficient activity against gram-positive pathogens |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344759/ https://www.ncbi.nlm.nih.gov/pubmed/32549350 http://dx.doi.org/10.3390/antibiotics9060327 |
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