M.P. Mingeot-Leclercq, P.M. Tulkens, F. Van Bambeke

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Presentation transcript:

M.P. Mingeot-Leclercq, P.M. Tulkens, F. Van Bambeke Ciprofloxacin-resistant J774 mouse macrophages show a reduction in the accumulation of quinolones through increased activity of an MRP-like transporter M. Heremans, J.M. Michot, M.P. Mingeot-Leclercq, P.M. Tulkens, F. Van Bambeke Unité de Pharmacologie cellulaire et moléculaire Université catholique de Louvain Brussels, Belgium

chemotherapeutic agents often need to reach an intracellular target… anticancer antibiotic bacteria mammal fungi antifungal

accordingly, they have been made amphipathic to diffuse through membranes… anticancer antibiotic bacteria mammal fungi antifungal

… but efflux pumps extrude amphipathic molecules and, hence, reduce their concentration in contact with the target… anticancer antibiotic bacteria mammal fungi antifungal

overexpression of efflux pumps is a well known mechanism of resistance anticancer antibiotic bacteria mammal fungi antifungal

ciprofloxacin is substrate of an MRP-like transporter in macrophages CIP transport is inhibited by ATP-depletion probenecid (inhibitor of organic anions transporters) MK 571 (inhibitor of MRP transporters) Michot et al, AAC 2004; 48:2 673-82.

is ciprofloxacin susceptible to select « resistance » in macrophages ? antibiotic mammal

CIP-resistant macrophages can be selected by chronical exposure to increasing CIP concentrations step-wise increase in CIP concentration several passages at each step time and drug consumming! multifactorial multidrug resistance Gottesman et al, Methods Enzymol. 1998 ; 292: 248-58

phenotypic characterization of the resistant cells accumulation of quinolones effect of efflux pump inhibitors reversibility of the resistant phenotype

quinolone differ in their accumulation in wild-type macrophages

quinolone accumulation is reduced to variable extent in CIP-resistant macrophages

probenecid increases CIP but not MXF accumulation in wild-type cells

higher probenecid concentrations are needed to restaure CIP accumulation in CIP-resistant cells

influence of probenecid on quinolone accumulation in wild-type and CIP-resistant cells

influence of MK571 on quinolone accumulation in wild-type and CIP-resistant cells

the CIP-resistant phenotype is not easily reversible

the CIP-resistant phenotype is not easily reversible

conclusions eucaryotic cells can become resistant to antibiotics ! macrophage resistance to CIP is mediated by an increase in expression / activity of an MRP – like transporter active efflux affects to variable levels the cellular accumulation of quinolones pharmacological consequences still under investigation ….

thanks to … MP Mingeot- Leclercq M Heremans JM Michot PM Tulkens F Van Bambeke