Phenothiazines as a solution for multidrug resistant tuberculosis: From the origin to present

Area of Science:

• Pharmacology and Medicinal Chemistry
• Infectious Diseases
• Microbiology

Background:

• The emergence of drug-resistant bacteria necessitates novel antimicrobial compounds.
• Phenothiazines, initially developed for antipsychotic properties, exhibit antimicrobial functions and are classified as non-antibiotics.
• Several phenothiazines, including thioridazine, have demonstrated antimycobacterial activity.

Purpose of the Study:

• To review the potential of thioridazine and its (-) enantiomer as treatments for drug-resistant tuberculosis.
• To explore the efficacy of low-dose thioridazine against Mycobacterium tuberculosis within macrophages.
• To assess the safety profile and therapeutic possibilities of thioridazine enantiomers in combating tuberculosis.

Main Methods:

• Review of in vitro and in vivo studies on phenothiazines, specifically thioridazine.
• Analysis of research investigating the antimycobacterial activity of thioridazine and its (-) form.
• Evaluation of studies focusing on the efficacy and safety of low-dose thioridazine against Mycobacterium tuberculosis.

Main Results:

• Thioridazine exhibits distinct antitubercular action, with low doses effectively killing tubercle bacilli inside macrophages.
• Low-dose thioridazine is devoid of the known central nervous system and cardiotoxic side-effects.
• The (-) thioridazine enantiomer demonstrates enhanced antimicrobial activity and reduced toxicity compared to the racemic form.

Conclusions:

• Thioridazine, particularly its (-) enantiomer, holds significant promise for treating drug-resistant tuberculosis.
• Combining thioridazine with existing antitubercular drugs could offer a strategy to eradicate Mycobacterium tuberculosis infections.
• Further research into thioridazine enantiomers could lead to novel, safe, and effective treatments for tuberculosis.