Cooperation between Prokaryotic (Lde) and Eukaryotic (MRP) Efflux Transporters in J774 Macrophages Infected with<i>Listeria monocytogenes</i>: Studies with Ciprofloxacin and Moxifloxacin

Lismond, Ann; Tulkens, Paul M.; Mingeot‐Leclercq, Marie‐Paule; Courvalin, Patrice; Bambeke, Françoise Van

doi:10.1128/aac.00105-08

Cited by 21 publications

(16 citation statements)

References 40 publications

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“…Beyond displaying a markedly reduced accumulation of ciprofloxacin, these ciprofloxacinresistant cells provide a protected environment against ciprofloxacin for Listeria monocytogenes (24). Moreover, we recently showed that this eukaryotic transporter can cooperate with a prokaryotic ciprofloxacin transporter to make intracellular L. monocytogenes still more resistant to the drug (20). In the present study, we now identify the ciprofloxacin efflux transporter as most likely being Mrp4.…”

mentioning

confidence: 68%

Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells

Márquez

Caceres

Mingeot‐Leclercq

et al. 2009

Antimicrob Agents Chemother

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Ciprofloxacin, the most widely used totally synthetic antibiotic, is subject to active efflux mediated by a MRP-like transporter in wild-type murine J774 macrophages. To identify the transporter among the seven potential Mrps, we used cells made resistant to ciprofloxacin obtained by long-term exposure to increasing drug concentrations (these cells show less ciprofloxacin accumulation and provide a protected niche for ciprofloxacin-sensitive intracellular Listeria monocytogenes). In the present paper, we first show that ciprofloxacin-resistant cells display a faster efflux of ciprofloxacin which is inhibited by gemfibrozil (an unspecific MRP inhibitor). Elacridar, at a concentration known to inhibit P-glycoprotein and breast cancer resistance protein (

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mentioning

confidence: 68%

Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells

Márquez

Caceres

Mingeot‐Leclercq

et al. 2009

Antimicrob Agents Chemother

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“…A variety of compounds that have demonstrated activity against either resistance-nodulation-division (RND) pumps or ABC transporter-type systems were tested. Specifically, phenylalanine-arginine ␤-naphthylamide (PA␤N) (11), 1-(1-naphthylmethyl)-piperazine (NMP) (12), reserpine (13), probenecid (14), verapamil (15), and gemfibrozil (16) were all tested for their abilities to potentiate MB-1 activity in the adaptation assay. Using concentrations that were previously shown to affect the activities of various efflux pumps, improvements in MB-1 activity were not observed when it was combined with PA␤N, NMP, probenecid, verapamil, or gemfibrozil.…”

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confidence: 99%

Potentiation of Antibacterial Activity of the MB-1 Siderophore-Monobactam Conjugate Using an Efflux Pump Inhibitor

Tomaras

Crandon

McPherson

et al. 2015

Antimicrob Agents Chemother

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Preliminary enthusiasm over the encouraging spectrum and in vitro activities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in in vivo efficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in Pseudomonas aeruginosa and provide evidence that efflux inhibition may circumvent this in vivo-relevant resistance liability.T he extent and severity of antibiotic resistance in Gram-negative pathogens require the development of innovative therapeutic interventions that not only circumvent existing clinically relevant resistance mechanisms but will also result in limited spontaneous resistance emergence. Although standard in vitro methodologies exist for predicting resistance development, translational deficiencies that can stem from their lack of in vivo physiological relevance are becoming increasingly apparent. We previously described the siderophore-monobactam conjugate MB-1 ( Fig. 1 [1]), which has broad-spectrum in vitro activities against multidrug-resistant (MDR) Gram-negative pathogens, including Pseudomonas aeruginosa, when tested using standard methods established by the Clinical and Laboratory Standards Institute (CLSI) (1). Unfortunately, we have also demonstrated that despite these encouraging in vitro activities, the efficacy of MB-1 in a neutropenic murine infection model was highly variable and not directly predictable from traditional in vitro activity assays (2). Instead, the development of a modified in vitro resistance frequency assay, which relies on the utilization of more in vivo-relevant iron conditions, has proven to be more predictive of the efficacy of MB-1 in vivo. Additionally, this assay has demonstrated a role for endogenous siderophores, such as pyoverdine, in mediating the adaptive cellular response that enables P. aeruginosa to transiently resist MB-1 activity (2). While these results suggest that the use of MB-1 as monotherapy is not a viable option, we have speculated about alternative strategies that may mitigate this adaptive response and resurrect MB-1 as a legitimate antibacterial agent. Among these potentiation-type approaches, we considered the idea that inhibiting endogenous siderophore functionality should circumvent the adaptation phenotype mediated by the competition for iron by native siderophore systems. Siderophore secretion into the extracellular milieu has been shown to be dependent on functional efflux pumps in Gram-negative bacteria (3-5). In the case of P. aeruginosa, the secretion of newly synthesized pyoverdine is accomplished by the ABC transporter-type efflux system encoded by pvdR, pvdT, and opmQ (6). Additionally, this system is responsible for pyoverdine recycling after successive rounds of iron acquisition and delivery (7).To prove that inhibiting the activity of this pump can potentiate the activity of MB-1, we generated a pvdRT-op...

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“…Alternatively, P-gp could potentially export molecules of bacterial origin outside infected cells and thus lead to immune activation of neighboring cells, essentially enhancing inflammation. In this respect, it was suggested that mammalian and bacterial MDRs share substrates and thus could potentially propagate innate immune responses by cotransporting bacterial ligands (60). Altogether, this study raises important questions regarding the function of P-gp in the development of innate immune responses and in interaction with bacterial pathogens.…”

Section: Discussionmentioning

confidence: 97%

“…Ciprofloxacin has been shown to inhibit L. monocytogenes growth in laboratory media (also shown in Fig. S2 in the supplemental material) and, likewise, intracellularly if added to THP-1 cells (58,60). Indeed, treating infected THP-1 cells with ciprofloxacin (4.5 M) strongly inhibited intracellular growth of L. monocytogenes (by 2.5 orders of magnitude) (Fig.…”

Section: P-gp Is Transcriptionally Induced Upon L Monocytogenes Infementioning

confidence: 99%

The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

et al. 2015

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bHuman multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they have additional functions in diverse physiological processes not related to drug efflux. Here, we show that the human multidrug transporter P-glycoprotein (P-gp) (also named MDR1 and ABCB1) is transcriptionally induced in the monocytic cell line THP-1 upon infection with the human intracellular bacterial pathogen Listeria monocytogenes. Notably, we found that P-gp is important for full activation of the type I interferon response elicited against L. monocytogenes bacteria. Both inhibition of P-gp function by verapamil and inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the type I response in infected cells. This function of P-gp was specific to type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to cyclic di-AMP (c-di-AMP), a molecule that was shown to be secreted by L. monocytogenes during infection and to trigger type I interferons. Moreover, P-gp was not involved in activation of other proinflammatory cytokines, such as those triggered by vacuolar-restricted L. monocytogenes or lipopolysaccharide (LPS). Taken together, these findings demonstrate a role for P-gp in proper development of an innate immune response against intracellular pathogens, highlighting the complexity in employing therapeutic strategies that involve inhibition of multidrug resistance (MDR) efflux pumps. Multidrug transporters mediate the active efflux of a wide range of drugs and xenobiotics, including antibiotics and chemotherapeutics (1). This permissive efflux ability engenders multidrug resistance (MDR)-a phenomenon that largely underlies the failure of various chemotherapeutic treatments (2-4). Human MDR transporters harbor an ATP-binding cassette (ABC), which defines the ABC-type superfamily, comprising more than 45 proteins in the human genome (5). Among these, several transporters have been extensively studied, such as the P-glycoprotein (P-gp) (also named MDR1 and ABCB1) (6), BCRP (ABCG2) (7), and MRP1 (ABCC1) (8), which were all shown to exhibit clinically relevant MDR functions (9). P-gp, encoded by the MDR1 gene, is the most prominent and best-characterized member of the ABCtype superfamily, first isolated in clinical cancers (6, 10). Aside from its well-documented multidrug resistance function in cancer cells, P-gp is naturally expressed in a variety of normal tissues and cells, including immune cells, such as macrophages, dendritic cells, T and B lymphocytes, and natural killer (NK) cells, and was shown to possess physiological functions beyond detoxification (11-15). Several studies have indicated roles for P-gp in lipid transport, intracellular trafficking of cholesterol, cell death, cell differentiation, and immune responses (16,17). Regarding the last, P-gp was shown to exhibit immunomodulatory activity and to influence the secretion of various inflammatory mediators,...

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Cooperation between Prokaryotic (Lde) and Eukaryotic (MRP) Efflux Transporters in J774 Macrophages Infected withListeria monocytogenes: Studies with Ciprofloxacin and Moxifloxacin

Cited by 21 publications

References 40 publications

Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells

Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells

Potentiation of Antibacterial Activity of the MB-1 Siderophore-Monobactam Conjugate Using an Efflux Pump Inhibitor

The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

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