Reduced intracellular activity of antibiotics against Listeria monocytogenes in multidrug resistant cells

Nichterlein, Thomas; Kretschmar, Marianne; Schadt, Aimée; Meyer, André; Wildfeuer, A; Laufen, H; Hof, Herbert

doi:10.1016/s0924-8579(98)00030-2

Cited by 23 publications

(13 citation statements)

References 16 publications

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“…Although various drug transporters are found in different cells (2), active drug efflux pumps, such as the ATP-binding cassette (ABC) transporter proteins MDR-1 and MRP-1, have an important role in the regulation of intracellular drug concentrations of antimicrobials (20,22,30). Localized at the plasma membranes of most cell types, MDR-1 and MRP-1 are distributed almost ubiquitously in numerous organs (19).…”

Section: Discussionmentioning

confidence: 99%

“…While diminished efficacy of antimicrobials against intracellular bacteria in cells overexpressing multidrug resistance protein 1 (MDR-1) has been reported, no direct correlation between oxygen availability and intracellular effectiveness of antimicrobials has been observed so far (20,22,30). Therefore, we investigated whether intracellular activities of recommended and alternative antimicrobials against C. trachomatis are maintained in a low-oxygen environment (16,34).…”

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confidence: 99%

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Impact of a Low-Oxygen Environment on the Efficacy of Antimicrobials against Intracellular Chlamydia trachomatis

Shima

Szaszák

Solbach

et al. 2011

Antimicrob Agents Chemother

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Emergence of chronic inflammation in the urogenital tract induced by Chlamydia trachomatis infection in females is a long-standing concern. To avoid the severe sequelae of C. trachomatis infection, such as pelvic inflammatory diseases (PID), ectopic pregnancies, and tubal infertility, antibiotic strategies aim to eradicate the pathogen even in asymptomatic and uncomplicated infections. Although first-line antimicrobials have proven successful for the treatment of C. trachomatis infection, treatment failures have been observed in a notable number of cases. Due to the obligate intracellular growth of C. trachomatis, reliable antimicrobial susceptibility assays have to consider environmental conditions and host cell-specific factors. Oxygen concentrations in the female urogenital tract are physiologically low and decrease further during an inflammatory process. We compared MIC testing and time-kill curves (TKC) for doxycycline, azithromycin, rifampin, and moxifloxacin under hypoxia (2% O 2 ) and normoxia (20% O 2 ). While low oxygen availability only moderately decreased the antichlamydial activity of azithromycin in conventional MIC testing (0.08 g/ml versus 0.04 g/ml; P < 0.05), TKC analyses revealed profound divergences for antibiotic efficacies between the two conditions. Thus, C. trachomatis was significantly less rapidly killed by doxycycline and azithromycin under hypoxia, whereas the efficacies of moxifloxacin and rifampin remained unaffected using concentrations at therapeutic serum levels. Chemical inhibition of multidrug resistance protein 1 (MDR-1), but not multidrug resistance-associated protein 1 (MRP-1), restored doxycycline activity against intracellular C. trachomatis under hypoxia. We suggest careful consideration of tissue-specific characteristics, including oxygen availability, when testing antimicrobial activities of antibiotics against intracellular bacteria.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Impact of a Low-Oxygen Environment on the Efficacy of Antimicrobials against Intracellular Chlamydia trachomatis

Shima

Szaszák

Solbach

et al. 2011

Antimicrob Agents Chemother

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“…In particular, the presence of a functional P-glycoprotein and its potential role in macrolide handling in polymorphonuclear leukocytes are controversial (4,14,21,38). It is interesting, however, that human KB and G-185 cells overexpressing P-glycoprotein show decreased levels of macrolide accumulation and correspondingly reduced levels of antimicrobial activity against intracellular forms of Listeria monocyto- genes (22). The influences of efflux proteins on cellular handling of macrolides and their effects on the intracellular activities of these antibiotics may therefore need to be studied systematically.…”

Section: Discussionmentioning

confidence: 99%

Influence of P-Glycoprotein Inhibitors on Accumulationof Macrolides in J774 MurineMacrophages

Seral

Michot

Chanteux

et al. 2003

Antimicrob Agents Chemother

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The influence of inhibitors of P-glycoprotein (verapamil [VE], cyclosporine [CY], and GF120918 [GF]) on the cell handling of macrolides (erythromycin [ERY], clarithromycin [CLR], roxithromycin [ROX], azithromycin [AZM], and telithromycin [TEL]) was examined in J774 murine macrophages. The net influx rates of AZM and TEL were increased from 2-to 3.5-fold in the presence of these inhibitors, but their efflux was slowed only marginally. At 3 h, the inhibitors increased the levels of AZM, ERY, and TEL accumulation approximately three-to fourfold (the effect of VE, however, was lower) but did not influence CLR accumulation ( 1). P-glycoprotein was detected by immunostaining at the cell surface as well as in intracellular vacuoles (endosomes and lysosomes). The data suggest that the influx of AZM, ERY, TEL, and ROX is adversely influenced by the activity of P-glycoprotein in J774 macrophages, resulting in suboptimal drug accumulation.Active drug transporters have been described in both procaryotic and eucaryotic cells. Originally described as conferring resistance to anticancer agents in cancer cells, antibiotics in bacteria, or antifungal agents in fungi, these proteins appear today to be part of a very general mechanism that cells have developed to protect themselves from invasion by diffusible, foreign molecules (for a review, see reference 37). In this context, the occurrence of antibiotic transporters in eucaryotic cells has become a common observation (7, 33). More specifically, P-glycoprotein (also referred to as MDR1) and MRP, which are expressed in most cell types and which transport a large variety of drugs, have received much attention. These two types of transporters belong to the superfamily of ATP binding cassette transporters and use ATP hydrolysis as an energy source (28). They play a key role in drug disposition by modulating drug transport through epithelia and other biological barriers to an extent that was completely unsuspected only a few years ago (1).Focusing on macrolides, erythromycin has been shown to be transported by P-glycoprotein in Caco-2 intestinal cells (29, 34). In parallel, erythromycin and azithromycin are capable of inhibiting the transport of various substrates of the P-glycoprotein in epithelial cells in vitro as well as in vivo (9,12,13,23,30,31,39). Yet, little is known about the role of efflux transporters in the handling of macrolides by macrophages, in which these drugs are known to accumulate in large amounts (2,3,20,24).In the present study, we have examined directly in macrophages the potential influence of P-glycoprotein and MRP on the accumulation and efflux of five macrolides of clinical interest. We used both broad-spectrum, nonspecific inhibitors of P-glycoprotein (verapamil and cyclosporine) and MRP (probenecid and gemfibrozil) and the specific P-glycoprotein modulator GF120918 (11, 15). We selected the murine J774 murine macrophage line since much is already known about the dispositions of macrolides in these cells (2,3,36). MATERIALS AND METHODS Cells.We used J77...

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“…Results from our group have confirmed the existence on the PMN membrane of an active saturable transport system common to all macrolides (and their recently synthesized derivatives, ketolides) which displays different affinities depending on the macrolide structure (398,399). Complete identification of this carrier has not yet been achieved, but there are data suggesting a link with a putative receptor belonging to the P-glycoprotein (P-gP) family (148,277,278). This P-gP-like receptor could operate in different ways by controlling entry and/or efflux depending on the cell type.…”

Section: Complex Game For Two or More Players With High Stakesmentioning

confidence: 99%

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

Labro¹

2000

Clinical Microbiology Reviews

151

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Reduced intracellular activity of antibiotics against Listeria monocytogenes in multidrug resistant cells

Cited by 23 publications

References 16 publications

Impact of a Low-Oxygen Environment on the Efficacy of Antimicrobials against Intracellular Chlamydia trachomatis

Impact of a Low-Oxygen Environment on the Efficacy of Antimicrobials against Intracellular Chlamydia trachomatis

Influence of P-Glycoprotein Inhibitors on Accumulationof Macrolides in J774 MurineMacrophages

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

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