TY - JOUR

T1 - A novel derivative of thioridazine shows low toxicity and efficient activity against gram‐positive pathogens

AU - Jørgensen, Nadia S.

AU - Saaby, Lasse

AU - Andersson, Anne M.

AU - Kromann, Sofie

AU - Sheikhsamani, Ehsan

AU - Permin, Anders

AU - Ronco, Troels

AU - Svenningsen, Søren W.

AU - Christensen, Jørn B.

AU - Olsen, Rikke H.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Gram‐positive pathogens

KW - Novel antimicrobial compound

KW - Thioridazine

U2 - 10.3390/antibiotics9060327

DO - 10.3390/antibiotics9060327

M3 - Journal article

C2 - 32549350

AN - SCOPUS:85086663415

VL - 9

JO - Antibiotics

JF - Antibiotics

SN - 2079-6382

IS - 6

M1 - 327

ER -