The purpose of this research was to find new EPIsof the AcrAB-TolC efflux system in groups aminederivatives of 5-arylidenehydantoin and5-arylideneimidazolone.In the first stage of the research 32 newderivatives of 5-arylidenehydantoin were obtained as aresult of modifications of the lead structure P2. Structuresof new derivatives were confirmed by using ; chromatographic and spectral methods (1H-NMR, 13CNMR,IR, LC-MS, elemental analysis).Theoretical screening of the toxicity risk as wellas the prediction of drug-like properties of testedderivatives were performed by using the OSIRISprogram.The activity of compounds was evaluated inmicrobiological studies. Three strains of Enterobacteraerogenes with different expressions of the AcrAB effluxpump. The first study carried out was a susceptibility testdetermining the MICs of compounds. Then the effect ofthe compounds on bacterial susceptibility to antibioticssuch as nalidixic acid, chloramphenicol, doxycycline anderythromycin was examined. After the most activecompounds were detected, their type of cooperation withantibiotics was determined based on isobolograms andthe FIC index calculated. The last of microbiologicalstudies performed was the real-time efflux (RTE) assaywhich used the fluorescent dye 1,2’-dinaphthylamine andallowed the functioning of the pump to be monitoreddirectly.The structure-activity relationship (SAR) analysiswhich was the last stage of the research allowed theidentification of structural fragments which could beessential for blocking the AcrAB.
Jagiellonian University Medical College. Faculty of Pharmacy. Department of Technology and Biotechnology of Drugs, Aix-Marseille University. Faculty of Medicine. UMR-MD1. Membrane Transporters, Chemoresistance and Drug-Design.
May 24, 2021
Dec 2, 2015
|ZB-123149||May 24, 2021|