Efflux pump inhibiting properties of racemic phenothiazine derivatives and their enantiomers on the bacterial AcrAB-TolC system.
OBJECTIVE
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 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.


METHODS
The main goal of the present study was to elucidate the role of chirality of N-hydroxyalkyl-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.


CONCLUSIONS
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.
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary spengler.gabriella@med.u-szeged.hu.
Gabriella
G
Spengler
Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Daniella
D
Takács
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Adám
A
Horváth
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Agnes Mira
AM
Szabó
Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Zsuzsanna
Z
Riedl
Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
György
G
Hajós
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
József
J
Molnár
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Katalin
K
Burián
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D024881:Drug Resistance, Bacterial; D048168:Escherichia coli K12 / Q000187:drug effects / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D010640:Phenothiazines / Q000737:chemistry* / Q000494:pharmacology*
C000596829:AcrAB-TolC protein, E coli; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; D010640:Phenothiazines
AcrAB-TolC efflux pump; Multidrug resistance; chirality; efflux pumps; enantiomers; phenothiazines