Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783556019488555008
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
work_keys_str_mv AT jørgensennadias anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT saabylasse anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT anderssonannem anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT kromannsofie anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT sheikhsamaniehsan anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT perminanders anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT roncotroels anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT svenningsensørenw anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT christensenjørnb anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT olsenrikkeh anovelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT jørgensennadias novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT saabylasse novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT anderssonannem novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT kromannsofie novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT sheikhsamaniehsan novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT perminanders novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT roncotroels novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT svenningsensørenw novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT christensenjørnb novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens
AT olsenrikkeh novelderivativeofthioridazineshowslowtoxicityandefficientactivityagainstgrampositivepathogens