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Volume 9
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10.3390/antibiotics9060327
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Article

A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens

by
Nadia S. Jørgensen
1,
Lasse Saaby
2,
Anne M. Andersson
1,
Sofie Kromann
1,
Ehsan Sheikhsamani
3,
Anders Permin
4,
Troels Ronco
1,
Søren W. Svenningsen
5,
Jørn B. Christensen
5 and
Rikke H. Olsen
1,*
1
Department of Veterinary and Animal Sciences, University of Copenhagen, Stigboejlen 4, 1870 Frederiksberg C, Denmark
2
Bioneer:FARMA, Department of Pharmacy, Universitetsparken 2, 2100 Copenhagen, Denmark
3
Department of animal science, Ferdowsi University, Mashhad IR-91779, Iran
4
Unibrains, Kollelevbakken 33, 2830 Virum, Denmark
5
Department of Chemistry, University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark
*
Author to whom correspondence should be addressed.
Antibiotics 2020, 9(6), 327; https://doi.org/10.3390/antibiotics9060327
Submission received: 6 May 2020 / Revised: 11 June 2020 / Accepted: 13 June 2020 / Published: 15 June 2020
(This article belongs to the Section Novel Antimicrobial Agents)
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Abstract

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.
Keywords: thioridazine; novel antimicrobial compound; Gram-positive pathogens thioridazine; novel antimicrobial compound; Gram-positive pathogens

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MDPI and ACS Style

Jørgensen, N.S.; Saaby, L.; Andersson, A.M.; Kromann, S.; Sheikhsamani, E.; Permin, A.; Ronco, T.; Svenningsen, S.W.; Christensen, J.B.; Olsen, R.H. A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens. Antibiotics 2020, 9, 327. https://doi.org/10.3390/antibiotics9060327

AMA Style

Jørgensen NS, Saaby L, Andersson AM, Kromann S, Sheikhsamani E, Permin A, Ronco T, Svenningsen SW, Christensen JB, Olsen RH. A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens. Antibiotics. 2020; 9(6):327. https://doi.org/10.3390/antibiotics9060327

Chicago/Turabian Style

Jørgensen, Nadia S., Lasse Saaby, Anne M. Andersson, Sofie Kromann, Ehsan Sheikhsamani, Anders Permin, Troels Ronco, Søren W. Svenningsen, Jørn B. Christensen, and Rikke H. Olsen. 2020. "A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens" Antibiotics 9, no. 6: 327. https://doi.org/10.3390/antibiotics9060327

APA Style

Jørgensen, N. S., Saaby, L., Andersson, A. M., Kromann, S., Sheikhsamani, E., Permin, A., Ronco, T., Svenningsen, S. W., Christensen, J. B., & Olsen, R. H. (2020). A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens. Antibiotics, 9(6), 327. https://doi.org/10.3390/antibiotics9060327

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