Antibacterial activity of antipsychotic agents, their association with lipid nanocapsules and its impact on the properties of the nanocarriers and on antibacterial activity.

Hassan Nehme,Viviane Cassisa,Alyaa A Ramadan,Catherine Guillet,Patrick Saulnier,Anita Umerska,Matthieu Eveillard,Karsten Becker

doi:10.1371/journal.pone.0189950

Abstract

Bacterial antibiotic resistance is an emerging public health problem worldwide; therefore, new therapeutic strategies are needed. Many studies have described antipsychotic compounds that present antibacterial activity. Hence, the aims of this study were to evaluate the in vitro antibacterial activity of antipsychotics belonging to different chemical families, to assess the influence of their association with lipid nanocapsules (LNCs) on their antimicrobial activity as well as drug release and to study the uptake of LNCs by bacterial cells. Antibacterial activity was evaluated against Gram-positive Staphylococcus aureus and Gram negative Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii by minimum inhibitory concentration (MIC) assay, and the capability of killing tested microorganisms was evaluated by time kill assay. LNCs were prepared by phase inversion method, and the antipsychotic agents were incorporated using pre-loading and post-loading strategies. Only phenothiazines and thioxanthenes showed antibacterial activity, which was independent of antibiotic-resistance patterns. Loading the nanocarriers with the drugs affected the properties of the former, particularly their zeta potential. The release rate depended on the drug and its concentration—a maximum of released drug of less than 40% over 24 hours was observed for promazine. The influence of the drug associations on the antibacterial properties was concentration-dependent since, at low concentrations (high nanocarrier/drug ratio), the activity was lost, probably due to the high affinity of the drug to nanocarriers and slow release rate, whereas at higher concentrations, the activity was well maintained for the majority of the drugs. Chlorpromazine and thioridazine increased the uptake of the LNCs by bacteria compared with blank LNCs, even below the minimum inhibitory concentration.

Highlights

Despite the abundance of antibiotics on the pharmaceutical market, their use has become increasingly limited due to the emergence of multidrug resistance among the microorganisms
In vitro antibacterial properties of antipsychotic drugs To date, research has focused on the antibacterial activity of phenothiazine derivatives
There were similarities in the antibacterial activity between the groups since their minimum inhibitory concentration (MIC) values were not different by more than one serial dilution, which was observed by comparing chlorpromazine with chlorprothixene and fluphenazine with flupentixol

Summary

Introduction

Despite the abundance of antibiotics on the pharmaceutical market, their use has become increasingly limited due to the emergence of multidrug resistance among the microorganisms. Some of them have devoted their efforts to the development of new semi-synthetic molecules to overcome specific bacterial resistance mechanisms by modulating the structures of existing antibiotics [2,3], while others have synthetized customized molecules for new bacterial targets [4]. Studies in this domain have brought to light that numerous compounds, belonging to different pharmacological families, bear significant antibacterial activity. It has been demonstrated that taking neuroleptic or antidepressant drugs was a risk factor for MRSA carriage [15]

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