Synergism between Antiplasmid Promethazine and Antibiotics In Vitro and In Vivo

Yvette Mandi

doi:10.4172/2167-0501.1000139

Abstract

Four large groups of antibiotics were developed for different targets of bacterial cells which differ from those of human cells. Uncontrolled use of antibiotics, resistance soon followed. Today, the majority of bacterial infections are caused by multidrug resistant bacterial isolates and result in serious treatment difficulties. The main cause for antibiotic resistance is the acquisition of plasmids which carry antibiotic resistant genes. These extra-chromosomal genetic elements can be eliminated by phenothiazines from antibiotic resistant bacteria by the selective inhibition of plasmid replication over that of the plasmid carrying bacterium at three different levels or steps as follows: 1. replication of plasmid DNA is destabilized due to the drug induced relaxation of super-helical structure of replicative form of plasmid DNA; 2. inhibition of partition of plasmid DNA during the cell division blocks the rolling circle type of distribution of plasmid into the two daughter cells; 3. inhibition of re-infection of plasmidless bacteria by blocking conjugation. The medical significance of plasmid elimination in vitro provides a method to isolate plasmid-free bacteria for biotechnology without any risks of mutation and opens a new perspective in rational drug design against multidrug resistant bacterial infections.

Highlights

Elimination of plasmids that carry antibiotic resistant genes renders the once infected bacterium susceptible to antibiotics to which the plasmid containing bacterium expressed resistance
The phenothiazine promethazine was initially selected and much studied for its in vitro antiplasmid effects because this compound is widely used in clinical practice and there are no contraindications when used in combination with other therapeutic compounds, other phenothiazines have been studied for potential anti-plasmid properties and some have been shown to express these properties in vivo
Many antibacterial chemotherapeutics are deemed to be ineffective globally and this, according to the recent WHO report [1] and presents a serious health problem that affects all countries of the world regardless of economic status There is a recognised urgent need for effective treatment alternatives for antibiotic resistant and multidrug resistant bacterial pathogens

Summary

Introduction

Elimination of plasmids that carry antibiotic resistant genes renders the once infected bacterium susceptible to antibiotics to which the plasmid containing bacterium expressed resistance. The antiplasmid activity of phenothiazine drugs that are used in clinical practice every daybecause of their known property to intercalate to DNA much in the same manner as ethidium bromide and acridines- we have studied these compounds for potential antiplasmid effects [4,5,6] During these studies, it was interesting to note that the growth of various Gram positive and Gram negative bacteria were inhibited by several phenothiazines e.g chlorpromazine, levo-mepromazine, diethazine and promethazine both in vitro and in vivo [6]. Of major importance is that these phenothiazine compounds were subsequently shown to possess antimutagenic properties This was the beginning of a series of experiments in the direction of rational drug design applicable for elimination of antibiotic resistance- and other plasmids for possible use in the medical practice to treat antibiotic resistant infections or to produce plasmid free bacteria for basic biotechnology free of any mutagenic effects. Antiplasmid compounds and antibiotics could have synergistic effects and could be recommended for the treatment of polyresistant infections without the risk of mutagenic effects

Bacterial species Acinetobacter anitratus Agrobacterium tumefaciens

In Vivo Experiments for Plasmid Elimination

Findings

In Vivo Studies in Pediatric and Adult Patients