Interplay between Chromosomal β-Lactamase and the MexAB-OprM Efflux System in Intrinsic Resistance to β-Lactams in
            <i>Pseudomonas aeruginosa</i>

Masuda, Nobuhisa; Gotoh, Naomasa; Ishii, Chie; Sakagawa, Eiko; Ohya, Satoshi; Nishino, Takeshi

doi:10.1128/aac.43.2.400

Cited by 95 publications

(37 citation statements)

References 23 publications

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“…In fact, it has been implicated to play a more significant role in resistance to β-lactam antibiotics than β-lactamases [53], [54]. Using the putative P. aeruginosa AmpR binding site [51], we identified a potential AmpR binding site upstream of the MexR repressor of this pump in the MexR-MexA intergenic region (5′ AAGCCTGCAAATGT 3′) indicating possible regulation of this pump by AmpR.…”

Section: Resultsmentioning

confidence: 99%

The Regulatory Repertoire of Pseudomonas aeruginosa AmpC ß-Lactamase Regulator AmpR Includes Virulence Genes

et al. 2012

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In Enterobacteriaceae , the transcriptional regulator AmpR, a member of the LysR family, regulates the expression of a chromosomal β-lactamase AmpC. The regulatory repertoire of AmpR is broader in Pseudomonas aeruginosa , an opportunistic pathogen responsible for numerous acute and chronic infections including cystic fibrosis. In addition to regulating ampC , P. aeruginosa AmpR regulates the sigma factor AlgT/U and production of some quorum sensing (QS)-regulated virulence factors. In order to better understand the ampR regulon, we compared the transcriptional profile generated using DNA microarrays of the prototypic P. aeruginosa PAO1 strain with its isogenic ampR deletion mutant, PAOΔ ampR . Transcriptome analysis demonstrates that the AmpR regulon is much more extensive than previously thought, with the deletion of ampR influencing the differential expression of over 500 genes. In addition to regulating resistance to β-lactam antibiotics via AmpC, AmpR also regulates non-β-lactam antibiotic resistance by modulating the MexEF-OprN efflux pump. Other virulence mechanisms including biofilm formation and QS-regulated acute virulence factors are AmpR-regulated. Real-time PCR and phenotypic assays confirmed the microarray data. Further, using a Caenorhabditis elegans model, we demonstrate that a functional AmpR is required for P. aeruginosa pathogenicity. AmpR, a member of the core genome, also regulates genes in the regions of genome plasticity that are acquired by horizontal gene transfer. Further, we show differential regulation of other transcriptional regulators and sigma factors by AmpR, accounting for the extensive AmpR regulon. The data demonstrates that AmpR functions as a global regulator in P. aeruginosa and is a positive regulator of acute virulence while negatively regulating biofilm formation, a chronic infection phenotype. Unraveling this complex regulatory circuit will provide a better understanding of the bacterial response to antibiotics and how the organism coordinately regulates a myriad of virulence factors in response to antibiotic exposure.

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Section: Resultsmentioning

confidence: 99%

The Regulatory Repertoire of Pseudomonas aeruginosa AmpC ß-Lactamase Regulator AmpR Includes Virulence Genes

et al. 2012

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“…However, resistance to these agents, imipenem and the quinolones in particular, is increasing [7,8]. The mechanisms underlying resistance to ␤-lactam agents include the production of ␤-lactamases, outer membrane permeability mutations and efflux pumps [9][10][11][12][13][14][15][16][17][18][19][20][21]. The latter two mechanisms also play a role in resistance to aminoglycosides and quinolones [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial resistance among non-fermentative Gram-negative bacilli isolated from the respiratory tracts of Italian inpatients: a 3-year surveillance study by the Italian Epidemiological Survey

Fadda

Spanu

Ardito

et al. 2004

International Journal of Antimicrobial Agents

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“…b-Lactam resistance is due to a variety of mechanisms; AmpC b-lactamase production [5][6][7], extended-spectrum b-lactamases [8], including carbapenemases [9][10][11][12], a barrier to diffusion at the outer membrane, and efflux mechanisms are among those described [13][14][15][16][17][18][19][20][21][22][23][24]. Loss of permeability [25] and active antimicrobial efflux may affect other types of drugs such as aminoglycosides or quinolones [26,27].…”

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confidence: 99%

Characterization ofPseudomonas aeruginosaIsolates: Occurrence Rates, Antimicrobial Susceptibility Patterns, and Molecular Typing in the Global SENTRY Antimicrobial Surveillance Program, 1997–1999

Gales¹,

Jones²,

Turnidge³

et al. 2001

CLIN INFECT DIS

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During 1997-1999, a total of 70,067 isolates (6631 Pseudomonas aeruginosa isolates) were analyzed in the SENTRY program by geographic region and body site of infection. The respiratory tract was the most common source of P. aeruginosa. P. aeruginosa isolation rates increased during the study interval. Europe was the only region to show a significant decline in beta-lactam and aminoglycoside susceptibility rates. There was a reduction in the rates of susceptibility of Canadian isolates to imipenem and of Latin American isolates to meropenem. A total of 218 multidrug-resistant P. aeruginosa isolates (MDR-PSA; resistant to piperacillin, ceftazidime, imipenem, and gentamicin) were observed; MDR-PSA occurrence rates (percentages of all isolates) ranged from 8.2% (Latin America) to 0.9% (Canada). No antimicrobial inhibited >50% of MDR-PSA strains. Molecular characterization of selected, generally resistant strains was performed. Isolates showing unique ribogroups were found in Europe, Latin America, and the United States, but clonal spread was documented in several medical centers.

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Interplay between Chromosomal β-Lactamase and the MexAB-OprM Efflux System in Intrinsic Resistance to β-Lactams in Pseudomonas aeruginosa

Cited by 95 publications

References 23 publications

The Regulatory Repertoire of Pseudomonas aeruginosa AmpC ß-Lactamase Regulator AmpR Includes Virulence Genes

The Regulatory Repertoire of Pseudomonas aeruginosa AmpC ß-Lactamase Regulator AmpR Includes Virulence Genes

Antimicrobial resistance among non-fermentative Gram-negative bacilli isolated from the respiratory tracts of Italian inpatients: a 3-year surveillance study by the Italian Epidemiological Survey

Characterization ofPseudomonas aeruginosaIsolates: Occurrence Rates, Antimicrobial Susceptibility Patterns, and Molecular Typing in the Global SENTRY Antimicrobial Surveillance Program, 1997–1999

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