Abstract. Background/Aim: Bacterial resistance to antibiotics has become a serious problem in antibacterial chemotherapy and resistance of bacteria to chemically- unrelated anti-microbial agents can be associated with the over-expression of efflux pumps. The simultaneous therapy with efflux pump inh

Background/Aim: Bacterial resistance to antibiotics has become a serious problem in antibacterial chemotherapy and resistance of bacteria to chemicallyunrelated anti-microbial agents can be associated with the over-expression of efflux pumps. The simultaneous therapy with efflux pump inhibitors (EPIs) could be a solution to improve the effectiveness of antibiotics. The response of an organism to an EPI often depends on how that molecule fits a particular site of a protein. Because enantiomers of a given compound rotate plane-polarized light in a solution by the same angle but in opposite directions, the rational drug design should take the chirality into account if there is a difference between the racemic compound and its enantiomers. Materials and Methods: The main goal of the present study was to elucidate the role of chirality of Nhydroxyalkyl-2-aminophenothiazines as effective EPIs by an automated method that uses the general efflux pump substrate ethidium bromide (EB) for the assessment of AcrAB-TolC system of wild-type Escherichia coli K-12 AG100. It has been shown that the most active EPIs among the N-hydroxyalkyl-2-aminophenothiazines were the compounds rac-3i, (+)-3i, and (–)-3i by modulating the AcrAB-TolC efflux pump. Conclusion: Comparison of effects of enantiomeric pairs revealed that their activities were similar to that of racemic derivatives. Moreover, there was no significant difference between the racemic compounds and their enantiomers related to their antibacterial and efflux pump inhibiting effects. Drug resistance has evidently appeared in response to selective pressures resulting from the excessive use of antibiotics and other anti-microbials. Multidrug efflux systems are responsible for clinically important resistance to chemotherapeutic agents in pathogenic bacteria, fungi, parasites and in human cancer cells. Efflux mechanisms of bacteria, namely pumping of anti-microbial agents out of the cells play an important role in anti-microbial resistance of pathogenic bacteria. Bacterial anti-microbial efflux systems can be divided into five superfamily classes, the major facilitator (MF) superfamily, the ATP-binding cassette (ABC) superfamily, the resistance-nodulation-division (RND) superfamily, the small multidrug resistance (SMR) superfamily and the multidrug and toxic compound extrusion (MATE) superfamily (1, 2). The use of efflux pump inhibitors (EPIs) has been investigated in order to improve the activity of antibiotics and the goal of the pharmacological chemistry has been the development of compounds that decrease the level of intrinsic resistance, significantly reverse acquired resistance and promote the decrease of emergence of multidrug resistant bacteria (3). Considering the main objective of using EPIs, these compounds should increase the susceptibility of bacteria to one or more antibiotics. The EPIs can address various efflux targets among which the followings can be emphasized: (i) expression of genes that induces multidrug resistance (MDR), (ii) assembly of membrane transporter complex responsible for drug efflux, (iii) energy involved in the activity of transporter proteins and (iv) inhibition of the movement of molecules inside the efflux channel by competition or blocking (4). 1071 Correspondence to: Gabriella Spengler, Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary. Tel: +36 62545115, Fax: +36 62545113, e-mail: spengler.gabriella@med.uszeged.hu