A novel derivative of thioridazine shows low toxicity and efficient activity against gram‐positive pathogens

Nadia S. Jørgensen, Lasse Saaby, Anne M. Andersson, Sofie Kromann, Ehsan Sheikhsamani, Anders Permin, Troels Ronco, Søren W. Svenningsen, Jørn B. Christensen, Rikke H. Olsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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 harmacodynamics studies are needed to clarify the clinical potential of this novel discovery.

Original languageEnglish
Article number327
JournalAntibiotics
Volume9
Issue number6
Number of pages11
ISSN2079-6382
DOIs
Publication statusPublished - 2020

Keywords

  • Gram‐positive pathogens
  • Novel antimicrobial compound
  • Thioridazine

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