Peptidomimetics of Efflux Pump Inhibitors Potentiate the Activity of Levofloxacin in Pseudomonas aeruginosa

Renau, Thomas E.; Léger, Roger; Yen, Rose; She, Miles W.; Flamme, Eric M.; Sangalang, Joan; Gannon, Carla L.; Chamberland, Suzanne; Lomovskaya, Olga; Lee, Ving J.

doi:10.1016/s0960-894x(02)00006-9

Cited by 76 publications

(34 citation statements)

References 11 publications

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“…In general, when combining antimicrobials with NMP at the highest concentrations (50 and 100 mg ml -1 ), the MICs decreased at least fourfold, not only in the isogenic E. coli strains but also in the E. coli field isolates with an MDR phenotype. Similar results have been obtained by some authors for the MICs of fluoroquinolones with NMP and other EPIs against Pseudomonas aeruginosa (Kriengkauykiat et al, 2005;Lomovskaya et al, 2001;Renau et al, 2002) and E. coli Sáenz et al, 2004;Schumacher et al, 2006).…”

Section: Discussionsupporting

confidence: 86%

“…These systems are protein exporters involved in the transport of lipophilic or amphiphilic molecules or toxic divalent cations with a broad spectrum of substrates (Renau et al, 2002;Van Bambeke et al, 2003). RND efflux pumps are organized as multicomponent systems, in which the efflux pump located in the inner membrane works in conjunction with a periplasmic fusion protein and an outer-membrane protein (Van Bambeke et al, 2003, 2010.…”

Section: Introductionmentioning

confidence: 99%

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Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains

Marchetti

Errecalde

Mestorino

2012

Journal of Medical Microbiology

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The objective of this study was to evaluate the interaction of the efflux pump inhibitor 1-(1-naphthylmethyl)-piperazine (NMP) when combined with different families of antimicrobial agents against isogenic strains and multidrug-resistant (MDR) Escherichia coli field strains isolated from animals. Laboratory isogenic strains of E. coli with different levels of expression of efflux pumps were used as quality controls. Ten MDR E. coli strains were collected from healthy animals in a cross-sectional study in four commercial dairy farms. The MICs of florfenicol, ciprofloxacin, tetracycline and ampicillin were determined by a serial microdilution method in Luria-Bertani broth in the presence or absence of NMP. NMP used with ampicillin exerted no effect on the isogenic or field strains. In most of the field MDR E. coli strains and in an acrAB-overexpressing (AG112) isogenic strain, the MICs of florfenicol, ciprofloxacin and tetracycline decreased at least fourfold when the antimicrobial was combined with the highest NMP concentrations. In the wild-type strain (AG100), there were no decreases of more than twice the MIC, whilst in strain AG100A, an efflux pump-deficient strain, the MIC did not change, regardless of the concentration of NMP used with these three antimicrobials. Thus, ampicillin was not affected by the efflux pump mechanism, whereas ciprofloxacin, tetracycline and florfenicol were shown to be substrates of efflux pumps, with a consequent significant reduction in MICs. Resistance could not be completely reversed in the E. coli field strains by NMP, probably because other resistance mechanisms were also present. However, in strain AG112, the MIC results demonstrated that NMP expressed an important synergistic activity with florfenicol. The reduction in florfenicol MIC value was sufficient to reverse antimicrobial resistance completely for AG112.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains

Marchetti

Errecalde

Mestorino

2012

Journal of Medical Microbiology

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“…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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“…The genomics provide many molecular targets to be identified and effectively screened: 5,96) peptide deformylase (PDF), 109) aminoacyl-tRNA synthetase, 110) fatty acid biosynthesis, 111) isoprenoid biosynthesis, 112) lipid A biosynthesis, 113) efflux pump, 114) aromatic amino acid biosynthesis, 96) DNA replication (GyrB subunit inhibitor), 115) protein secretion, 116) cell wall biosynthesis (sortase), 117) proteasome, 118) glyoxylate cycle, 119) and signal networks (two-component systems and quorum sensing pathways). 120,121) 1.…”

Section: New Targetsmentioning

confidence: 99%

Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development

Yoneyama

Katsumata

2006

Bioscience, Biotechnology, and Biochemistry

236

196

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Peptidomimetics of Efflux Pump Inhibitors Potentiate the Activity of Levofloxacin in Pseudomonas aeruginosa

Cited by 76 publications

References 11 publications

Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains

Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains

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

Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development

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