Inhibitors of Efflux Pumps in Pseudomonas aeruginosa Potentiate the Activity of the Fluoroquinolone Antibacterial Levofloxacin

Renau, Thomas E.; Léger, Roger; Flamme, Eric M.; Sangalang, Joan; She, Miles W.; Yen, Rose; Gannon, Carla L.; Griffith, David E.; Chamberland, Suzanne; Lomovskaya, Olga; Hecker, Scott J.; Lee, Ving J.; Ohta, Toshiharu; Nakayama, Kiyoshi

doi:10.1021/jm9904598

Cited by 241 publications

(230 citation statements)

References 27 publications

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“…This is probably due to the fact that the inhibition of the MexAB-OprM efflux pump decreased intrinsic resistance to such a degree that the effect of single mutations affecting fluoroquinolone resistance was insufficient to make cells resistant enough to survive at the tested concentrations. This same phenomenon was demonstrated with similar compounds in a neutropenic mouse model (78,209). Also, C. jejuni displayed a 1,000-fold reduction in the emergence of resistant colonies when simultaneously exposed to erythromycin and PA␤N (151).…”

Section: Negating Efflux Pump Activitysupporting

confidence: 67%

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

2012

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SUMMARY The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms.

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Section: Negating Efflux Pump Activitysupporting

confidence: 67%

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

2012

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“…In contrast, no differences in the susceptibilities to coumestrol and berberine were detected, indicating that these compounds are probably not substrates of this pump. To corroborate this fact and given that antimicrobial activity of plant secondary metabolites is often masked by the concerted action of multiple MDR efflux pumps with similar substrate profiles (47), the MICs were determined in the presence of the MC 207110 inhibitor, known to inhibit certain RND efflux pumps (48,49). In the presence of this inhibitor, the susceptibilities of both strains to phloretin, quercetin, naringenin, and even coumestrol dramatically increased.…”

Section: Resultsmentioning

confidence: 99%

Effector-Repressor Interactions, Binding of a Single Effector Molecule to the Operator-bound TtgR Homodimer Mediates Derepression

Terán¹,

Krell

Ramos

et al. 2006

Journal of Biological Chemistry

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The RND family transporter TtgABC and its cognate repressor TtgR from Pseudomonas putida DOT-T1E were both shown to possess multidrug recognition properties. Structurally unrelated molecules such as chloramphenicol, butyl paraben, 1,3-dihydroxynaphthalene, and several flavonoids are substrates of TtgABC and activate pump expression by binding to the TtgR-operator complex. Isothermal titration calorimetry was employed to determine the thermodynamic parameters for the binding of these molecules to TtgR. Dissociation constants were in the range from 1 to 150 M, the binding stoichiometry was one effector molecule per dimer of TtgR, and the process was driven by favorable enthalpy changes. Although TtgR exhibits a large multidrug binding profile, the plantderived compounds phloretin and quercetin were shown to bind with the highest affinity (K D of around 1 M), in contrast to other effectors (chloramphenicol and aromatic solvents) for which exhibited a more reduced affinity. Structure-function studies of effectors indicate that the presence of aromatic rings as well as hydroxyl groups are determinants for TtgR binding. The binding of TtgR to its operator DNA does not alter the protein effector profile nor the effector binding stoichiometry. Moreover, we demonstrate here for the first time that the binding of a single effector molecule to the DNA-bound TtgR homodimer induces the dissociation of the repressor-operator complex. This provides important insight into the molecular mechanism of effector-mediated derepression.

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“…To search for enhanced activity of the efflux pump in strains, the reduction of the MIC of levofloxacin was determined using the efflux inhibitor L-phenylalanine-Larginine-β-naphthylamine (MC-207,110) (SigmaAldrich, Tokyo) at a concentration of 20.0 µg/ml in Muller Hinton media (10,18). The contribution of the efflux pump was judged significant if the inhibitor decreased the MIC of levofloxacin eightfold or greater (17,19).…”

Section: Methodsmentioning

confidence: 99%

Molecular Characterization of Imipenem‐Resistant Pseudomonas aeruginosa in Hiroshima, Japan

Ohara

Kouda

Onodera

et al. 2007

Microbiology and Immunology

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Nosocomial infections by Pseudomonas aeruginosa continue to be a widespread problem in Asia, North and South America, and Europe. Carbapenems are the most potent β-lactams against P. aeruginosa because its strong affinity to penicillin binding proteins, stability against most serine β-lactamases and high permeability across the outer membrane (7,8). However, intensive use of the carbapenems facilitated the emergence of carbapenem-resistant P. aeruginosa. Low level resistance to imipenem (MIC, 8 to 32 µg/ml) in P. aeruginosa is mostly due to reduced uptake of the drug as a result of loss of the porin OprD (8). This mechanism correlates with continued expression of AmpC β-lactamase. Resistance to meropenem but not imipenem may also arise via overexpression of the MexA-MexBOprM efflux pump (14). High level resistance to carbapenems (MICϾ32 µg/ml) can be caused by the presence of metallo-β-lactamase, which exhibits a broadspectrum resistance to β-lactams including carbapenems. Metallo-β-lactamase-producing P. aeruginosa Abstract: Pseudomonas aeruginosa showing resistance to imipenem were found in 100 of 1,058 strains (9.5%) from six hospitals (a-f) in Hiroshima City, Japan. Of the 100 strains, 14 (14%) were double disk synergy test positive using sodium mercaptoacetic acid disks, and 18 (18%) were bla IMP-1 or blaVIM-2 allele positive by polymerase chain reaction (PCR). Among 100 imipenem-resistant strains, 32 were categorized into multi-drug resistant strains, in which 13 were positive for the metallo-␤-lactamase gene. Fifty-one strains (51%) among the 100 imipenem-resistant strains had elevated RND efflux pump activity against levofloxacin. But only 6 of 51 strains were classified as multi-drug resistant strains. The pulsed field gel electrophoresis analysis of the SpeI-digested DNA from the 100 isolates suggested not only clonal spread but spread of heterogeneous clones started to contribute to the prevalence of metallo-␤-lactamase producing P. aeruginosa strains in Japanese hospitals.

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Inhibitors of Efflux Pumps in Pseudomonas aeruginosa Potentiate the Activity of the Fluoroquinolone Antibacterial Levofloxacin

Cited by 241 publications

References 27 publications

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

Effector-Repressor Interactions, Binding of a Single Effector Molecule to the Operator-bound TtgR Homodimer Mediates Derepression

Molecular Characterization of Imipenem‐Resistant Pseudomonas aeruginosa in Hiroshima, Japan

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