# Double‐Duty Drugs: Repositioning Antipsychotics to Combat Bacterial Infections

## TL;DR

This paper reviews how antipsychotic drugs might be repurposed to fight bacterial infections by exploring their antibacterial mechanisms and challenges.

## Contribution

The paper systematically reviews the antibacterial mechanisms of antipsychotics and highlights gaps in current research.

## Key findings

- Antipsychotics can disrupt bacterial plasma membranes and affect ionic balance, reducing viability.
- They inhibit efflux pumps and may interfere with DNA replication and cell wall formation.
- Higher doses are needed for antibacterial effects, raising safety and resistance concerns.

## Abstract

This article provides a comprehensive review of the antibacterial properties of antipsychotics, exploring proposed pathways and mechanisms of action. While experimental evidence supports certain mechanisms, such as efflux pump inhibition, others, including the impact on the respiratory chain in
M. tuberculosis
and cell wall inhibition, remain insufficiently substantiated.

Current research primarily relies on in vitro experiments, with limited exploration of in vivo effects. The influence of antipsychotics on gut microbiota poses a significant concern, as alterations may lead to dysbiosis, which has been linked to various illnesses. Additionally, antimicrobial drugs can exert selective pressure, fostering resistance in bacterial strains.

Repositioning antipsychotics as antimicrobials is further complicated by the need for higher doses than those approved for therapeutic use in humans, raising safety concerns. The use of antipsychotics in non‐psychotic populations is particularly problematic due to a lack of proven efficacy and potential adverse effects, such as metabolic disturbances, movement disorders, and sleep issues.

These challenges highlight the need for extensive in vivo and clinical studies to evaluate the antibacterial potential of antipsychotics, ensuring safety and efficacy. Careful monitoring and a balanced risk–benefit analysis are essential when considering antipsychotics for antimicrobial purposes.

Antipsychotics can exert antibacterial effects via several mechanisms: (1, 2) Due to their amphiphilic and cationic characteristics, antipsychotics can negatively affect the integrity of the plasma membrane by disrupting its structure and electrochemical potential. Subsequently, cellular shape and intracellular ionic balance vanish leading to a decrease in bacterial viability. (3) Antipsychotics can interact with the protein calmodulin and change Ca2+‐dependent cascades. (4) Additionally, they possess the ability to hinder processes associated with nucleic acids, such as DNA replication and RNA translation. (5) Antipsychotics also target the efflux pump, a significant mechanism through which bacteria develop resistance. These medications can inhibit the efflux system by interacting directly with their subunits and altering their activity. (6) They may impede the replication of plasmids as well. (7) Additionally, they have been demonstrated to hinder cell wall formation by binding to PBP; however, more investigation is needed to clarify this mechanism. (8) Eventually, antipsychotics can exert their antibiotic effect by altering energy‐producing pathways via disruption in membrane‐bound ATPase pumps.