# Phenothiazine Derivatives: The Importance of Stereoisomerism in the Tolerance and Efficacy of Antimicrobials

## TL;DR

This study shows that the S-enantiomer of a phenothiazine derivative has better in vivo tolerance and similar antimicrobial activity compared to the racemic form.

## Contribution

The study demonstrates the importance of using purified enantiomers over racemic mixtures for improved antimicrobial drug tolerance and efficacy.

## Key findings

- The maximum tolerable concentration of (S)-JBC 1847 was five times higher than the racemic form.
- The in vivo efficacy of (S)-JBC 1847 was comparable to vancomycin in a mouse MRSA model.
- Antimicrobial activity of (S)-JBC 1847 was similar to or slightly better than the racemic form in vitro.

## Abstract

Stereoisomers are molecules that are identical in atomic constitution and bonding. The biological properties may, however, differ significantly between two enantiomers (individual stereoisomers). JBC 1847, a phenothiazine derivative with strong antimicrobial activity against Gram-positive bacteria, exists in two enantiomers, S and R. Under standard chemical synthesis (S)-and (R)-JBC 1847 will be present in 50/50 amount (racemic). In this study, we have investigated the antimicrobial activity, the in vivo tolerance and therapeutic efficacy of purified (S)-JBC 1847. Compared to JBC 1847 racemic, the antimicrobial activity of (S)-JBC 1847 in vitro was in the same range or slightly increased, while the maximum tolerable concentration in vivo was five times higher for (S)-JBC 1847 (5 mg/kg versus 20 mg/kg bodyweight). Furthermore, the in vivo efficacy of (S)-JBC 1847 in a mouse peritonitis MRSA model was comparable to the activity of vancomycin. In conclusion, the antimicrobial activity and tolerance of a medical stereoisomeric compound may be significantly different using purified enantiomers compared with the racemic state.

The online version contains supplementary material available at 10.1007/s12088-024-01309-3.