Characterization of the active efflux of fluoroquinolones in eukaryotic cells
(2012)
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- Authors
- Supervisors
- Van Bambeke, Françoise
- Abstract
- (en) The subject of my thesis consisted in studying the role of multidrug transporters in the active efflux of fluoroquinolones, a class of antibiotics. To this effect, the laboratory obtained resistant cells by chronic exposure ciprofloxacin (CIP-R) and moxifloxacin (MXF-R). Previous results obtained in the laboratory showed that CIP-R cells overexpress the Mrp4 transporter which leads to the efflux of the fluoroquinolone outside of the cells. The objectives of the thesis were (i) to characterize MXF-R cells and to better determine resistance mechanisms developed by CIP-R and MXF-R cells, and (ii) to investigate the influence of the fluoroquinolone’s structure with respect to their recognition by the Mrp4 transporter. Results obtained have shown that the overexpression of Mrp4 in CIP-R cells was due to a duplication of the gene coding for the protein. Then, we demonstrated that MXF-R cells displayed an under expression of the Mrp4 transporter which does not affect the accumulation of moxifloxacin. The resistance mechanism in MXF-R cells could be an alteration of the type II topoisomerase (which was less sensitive to etoposide, a specific inhibitor for this enzyme) in those cells. We have demonstrated for the second objective that the intracellular accumulation of fluoroquinolones was not predictive of their intracellular activity. We were not able to determine one physicochemical parameter which could govern the sensitivity to efflux of fluoroquinolones by Mrp4. But we have shown that Mrp4 and transporters from Gram positive bacteria such as NorA in Staphylococcus aureus and PatA/PatB in Streptococcus pneumonia share the same molecular determinants for fluoroquinolone recognition.
- Affiliations
Citations
Vallet, C. (2012). Characterization of the active efflux of fluoroquinolones in eukaryotic cells. https://hdl.handle.net/2078.5/158972