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  • 1 Faculty of Medicine, University of Szeged Department of Medical Microbiology and Immunobiology Szeged Hungary
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The main target of the thesis was to investigate the drug resistance reversal on prokaryotic and eukaryotic model organisms. Based on DNA and protein complex formation properties of the given compounds the plasmid elimination of bacteria and the modification of the drug transporter proteins various experimental systems have been studied in bacteria and tumor cells.It was found that E. coli cells isolated from clinical specimen were less sensitive for the plasmid elimination than the laboratory strain carrying F prime plasmid, however, there was a complex formation between the antiplasmid compounds and the plasmid DNA isolated from both the clinical and laboratory strains. In addition there was a difference between the curing effect of two phenothiazines – the PMZ and TFP – on some E. coli strains in this study. The mechanism of action of different antiplasmid compounds was investigated on model nucleic acids such as calf thymus DNA and plasmid DNA. The pyrido[3,2-g] quinoline and phenothiazine derivatives seemed to have a complex formation with the model nucleic acids. Some of the compounds modified the activity of membrane efflux proteins. Based on the effect of trifluoromethyl ketones earlier studied my attention was focused on the combination of the trifluoromethyl ketone proton pump inhibitor TF18 with well-known antiplasmid compounds such as promethazine, trifluoperazine and 9-aminoacridine. In checkerboard studies the interaction between proton pump inhibitor and tricyclic compounds has been examined and it turned out that the interaction of proton pump inhibitor and trifluoperazine exerted synergistic antibacterial and plasmid curing effect on E. coli doxycycline resistant clinical strain due to the alteration of activity of membrane transporters. The role of proton pump system of the bacterial membrane was studied on Helicobacter pylori strains. The trifluoroketone proton pump inhibitor was able to block the proton motive forces and the activity of flagellar motor of both clarithromycin sensitive and resistant isolates of Helicobacter pylori . Since swimming was more sensitive to the inhibition than tumbling, I can suppose that TF18 works as an un-coupler in biological motor. The sensitivity of MDR1 type of eukaryotic ABC-transporter to resistance modifiers was studied on cancer cells. The synthetic benzo[b]-1,8-naphthyridine, pyridoquinoline, aza-oxafluorene and pregnane derivatives exerted reversing action of P-glycoprotein. Furthermore natural compounds, like coumarin derivatives and some fractions of persimmon extracts have been found to be potent resistance reversal agents against tumour cells.

  • Misbahi, H., Brouant, P., Hevér, A., Molnár, A., Wolfárd, K., Spengler, G., Mefetah, H., Molnár, J., Barbe, J.: Benzo[b]-1,8-naphthyridine derivatives: synthesis and reversal activity on multidrug resistance. Anticancer Res., 2002, 22 , 2097–2101.

    Barbe J. , 'Benzo[b]-1,8-naphthyridine derivatives: synthesis and reversal activity on multidrug resistance ' (2002 ) 22 Anticancer Res. : 2097 -2101.

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  • Rao, B. K., Motohashi, N., Kawase, M., Spengler, G., Molnár, J.: Multidrug resistance reversal in mouse lymphoma cells by Indian tea leaves, Indian coffee seeds and chicory. Oriental Pharmacy and Experimental Medicine, 2003, 3 , 100–105.

    Molnár J. , 'Multidrug resistance reversal in mouse lymphoma cells by Indian tea leaves, Indian coffee seeds and chicory ' (2003 ) 3 Oriental Pharmacy and Experimental Medicine : 100 -105.

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  • Kawase, M., Motohashi, N., Satoh, K., Sakagami, H., Tani., S., Shirataki, Y., Kurihara, T., Spengler, G., Wolfárd, K., Molnár, J.: Biological activity of persimmon (Diospyros kaki) peel extracts. Phytother. Res., 2003, 17 , 495–500.

    Molnár J. , 'Biological activity of persimmon (Diospyros kaki) peel extracts ' (2003 ) 17 Phytother. Res. : 495 -500.

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  • Spengler, G., Miczák, A., Hajdú, F., Kawase, M., Amaral, L., Molnár, J.: Enhancement of plasmid curing by 9-aminoacridine and two phenothiazines in the presence of proton pump inhibitor 1-(2-benzoxazolyl)-3,3,3-trifluoro-2-propanone. Int. J. Antimicrob. Agents, 2003, 22 , 223–227.

    Molnár J. , 'Enhancement of plasmid curing by 9-aminoacridine and two phenothiazines in the presence of proton pump inhibitor 1-(2-benzoxazolyl)-3,3,3-trifluoro-2-propanone ' (2003 ) 22 Int. J. Antimicrob. Agents : 223 -227.

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  • Madureira, A. M., Spengler, G., Molnár, A., Varga, A., Molnár, J., Abreu, P., Ferreira, M. J.: Effects of cycloartanes on reversal of multidrug resistance and apoptosis induction on mouse lymphoma cells. Anticancer Research, 2004, 24 , 865–72.

    Ferreira M. J. , 'Effects of cycloartanes on reversal of multidrug resistance and apoptosis induction on mouse lymphoma cells ' (2004 ) 24 Anticancer Research : 865 -72.

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  • Spengler, G., Molnár, A., Klausz, G., Mándi, Y., Kawase, M., Motohashi, N., Molnár, J.: Inhibitory action of a new proton pump inhibitor, trifluoromethyl ketone derivative, against the motility of clarithromycin-susceptible and -resistant Helicobacter pylori . Int. J. Antimicrob. Agents, 2004, 23 , 631–633.

    Molnár J. , 'Inhibitory action of a new proton pump inhibitor, trifluoromethyl ketone derivative, against the motility of clarithromycin-susceptible and -resistant Helicobacter pylori ' (2004 ) 23 Int. J. Antimicrob. Agents : 631 -633.

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  • Molnár, J., Molnár, A., Spengler, G., Mándi, Y.: Infectious plasmid resistance and efflux pump mediated resistance. Acta Microbiol. et Immunol. Hung., 2004, 51 , 333–349.

    Mándi Y. , 'Infectious plasmid resistance and efflux pump mediated resistance ' (2004 ) 51 Acta Microbiol. et Immunol. Hung. : 333 -349.

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  • Spengler, G., Molnár, A., Klausz, G., Mándi, Y., Kawase, M., Motohashi, N., Molnár, J.: The antimotility action of a trifluoromethyl ketone on some Gram-negative bacteria. Acta Microbiol. Immunol. Hung., 2004, 51 , 351–358.

    Molnár J. , 'The antimotility action of a trifluoromethyl ketone on some Gram-negative bacteria ' (2004 ) 51 Acta Microbiol. Immunol. Hung. : 351 -358.

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  • Sharples, D., Spengler, G., Molnár, J., Antal, Zs., Molnár, A., Kiss, T. J., Szabó, A. J., Hilgeroth, A., Gallo, S., Mahamoud, A., Barbe, J.: The interaction between resistance modifiers such as pyrido[3,2-g]quinoline, aza-oxafluorene and pregnane derivatives with DNA, plasmid DNA and tRNA. Eur. J. Med. Chem., 2005, 40 , 195–202.

    Barbe J. , 'The interaction between resistance modifiers such as pyrido[3,2-g]quinoline, aza-oxafluorene and pregnane derivatives with DNA, plasmid DNA and tRNA ' (2005 ) 40 Eur. J. Med. Chem. : 195 -202.

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  • Kawase, M., Sakagami, H., Motohashi, N., Hauer, H., Chatterjee, S., Spengler, G., Varadi, A., Molnár, A., Molnár, J.: Coumarin derivatives with tumour-specific cytotoxicity and multidrug resistance reversal activity. In Vivo, 2005, 19 , 705–712.

    Molnár J. , 'Coumarin derivatives with tumour-specific cytotoxicity and multidrug resistance reversal activity ' (2005 ) 19 In Vivo : 705 -712.

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