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.

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.

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