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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2003-4-30
pubmed:abstractText
Antibiotic efflux pumps expressed in eukaryotic cells can decrease the intracellular accumulation of the corresponding drugs and therefore impair their activity against intracellular bacteria. We have investigated whether verapamil (an inhibitor of P-glycoprotein) and gemfibrozil (an inhibitor of multidrug resistance proteins (MRP) and other organic anion transporters), can modulate the intracellular activity of azithromycin and ciprofloxacin against Listeria monocytogenes and Staphylococcus aureus in J774 macrophages. In parallel, we have measured the cell accumulation and subcellular distribution of both drugs. Antibiotics were used at equipotent extracellular concentrations (from 0.5 x to 10 x MIC) to allow for pharmacological comparisons. Azithromycin was bacteriostatic against L. monocytogenes and slightly bactericidal against S. aureus. Verapamil did not improve the maximal activity of azithromycin but allowed it to reach a similar effect at extracellular concentrations about seven-fold lower in both models. Azithromycin was predominantly localized in cell granules (66%), the remainder being in the cytosol and in the 'nuclei/unbroken cells' fraction. Verapamil increased the cellular accumulation of azithromycin by almost 2.4-fold without modifying its subcellular distribution. Ciprofloxacin displayed a strong concentration-dependent bactericidal activity in both models. Gemfibrozil increased ciprofloxacin activity almost 2.5-fold against L. monocytogenes, but not against S. aureus. Ciprofloxacin was predominantly (65%) distributed in the cytosol. Gemfibrozil increased ciprofloxacin total accumulation by approximately 2.4-fold, but the excess was only found in the cytosol. Inhibition of efflux pumps may be a useful strategy to improve antibiotic efficacy against intracellular bacteria when increased accumulation can be obtained in the compartment where bacteria sojourn.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0305-7453
pubmed:author
pubmed:issnType
Print
pubmed:volume
51
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1167-73
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Influence of P-glycoprotein and MRP efflux pump inhibitors on the intracellular activity of azithromycin and ciprofloxacin in macrophages infected by Listeria monocytogenes or Staphylococcus aureus.
pubmed:affiliation
Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 73.70 Avenue E. Mounier 73, B-1200 Brussels, Belgium.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't