Joseph Molnár, Yvette Mándi, Gabriella Spengler, Leonard Amaral1,Ibolya Haszon, Sándor Turi and Miklós Kásler
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 majorities 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 plasmid less bacteria by blocking conjugation. The medical importance of in vivo anti-plasmid effects of promethazine was shown, and resulted in synergism between promethazine and gentamycin treatment. The frequently recurring pyelonephritis was cured in children. All the in vivo studies employing promethazine described in this review have been approved by Ethics Committee of Clinic and Hospital where therapy took place.
The 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.
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