Structural and Functional Characterization of Pseudomonas aeruginosa Global Regulator AmpR

Caille, Olivier; Zincke, Diansy; Merighi, Massimo; Balasubramanian, Deepak; Kumari, Hansi; Kong, Kok Fai; Silva-Herzog, Eugenia; Narasimhan, Giri; Schneper, Lisa; Lory, Stephen; Mathee, Kalai

doi:10.1128/jb.01997-14

Cited by 40 publications

(49 citation statements)

References 86 publications

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“…One of the targets might be the transcriptional regulator AmpR, a potential inner membrane-associated protein (58). This hypothesis is supported by the observations that in the presence of ␤-lactams, the ⌬rpoN mutant stimulated a significant increase in the levels of the ampR gene and the gene encoding ␤-lactamase, ampC (58), suggesting that this increase in ampR and ampC levels might aid in explaining the carbapenem-tolerant phenotype of the ⌬rpoN mutant. Additionally, the ⌬ampR mutant exerted a negative effect on the expression of the major QS regulators LasR, RhlR, PqsR, and PQS and the pyochelin and pyoverdine genes (59).…”

Section: Discussionsupporting

confidence: 59%

RpoN Modulates Carbapenem Tolerance in Pseudomonas aeruginosa through Pseudomonas Quinolone Signal and PqsE

Viducic

Murakami

Amoh

et al. 2016

Antimicrob Agents Chemother

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bThe ability of Pseudomonas aeruginosa to rapidly modulate its response to antibiotic stress and persist in the presence of antibiotics is closely associated with the process of cell-to-cell signaling. The alternative sigma factor RpoN ( 54 ) is involved in the regulation of quorum sensing (QS) and plays an important role in the survival of stationary-phase cells in the presence of carbapenems. Here, we demonstrate that a ⌬rpoN mutant grown in nutrient-rich medium has increased expression of pqsA, pqsH, and pqsR throughout growth, resulting in the increased production of the Pseudomonas quinolone signal (PQS). The link between pqsA and its role in carbapenem tolerance was studied using a ⌬rpoN ⌬pqsA mutant, in which the carbapenem-tolerant phenotype of the ⌬rpoN mutant was abolished. In addition, we demonstrate that another mechanism leading to carbapenem tolerance in the ⌬rpoN mutant is mediated through pqsE. Exogenously supplied PQS abolished the biapenem-sensitive phenotype of the ⌬rpoN ⌬pqsA mutant, and overexpression of pqsE failed to alter the susceptibility of the ⌬rpoN ⌬pqsA mutant to biapenem. The mutations in the ⌬rpoN ⌬rhlR mutant and the ⌬rpoN ⌬pqsH mutant led to susceptibility to biapenem. Comparison of the changes in the expression of the genes involved in QS in wild-type PAO1 with their expression in the ⌬rpoN mutant and the ⌬rpoN mutant-derived strains demonstrated the regulatory effect of RpoN on the transcript levels of rhlR, vqsR, and rpoS. The findings of this study demonstrate that RpoN negatively regulates the expression of PQS in nutrient-rich medium and provide evidence that RpoN interacts with pqsA, pqsE, pqsH, and rhlR in response to antibiotic stress.

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Section: Discussionsupporting

confidence: 59%

RpoN Modulates Carbapenem Tolerance in Pseudomonas aeruginosa through Pseudomonas Quinolone Signal and PqsE

Viducic

Murakami

Amoh

et al. 2016

Antimicrob Agents Chemother

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“…In addition, new players such as ampP, ampDh2 and ampDh3 have been identified in P. aeruginosa [139,151]. Moreover, the localization of P. aeruginosa AmpR as an inner membrane protein with the helix-turn-helix domain in the cytoplasm and effector-binding domain in the periplasm leads to unique questions as to how the effector molecules are transported to their binding sites on AmpR [212].…”

Section: Cell-wall Recycling and Antibiotic Resistancementioning

confidence: 99%

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Dhar

Kumari

Balasubramanian

et al. 2018

Journal of Medical Microbiology

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The bacterial cell-wall that forms a protective layer over the inner membrane is called the murein sacculus -a tightly crosslinked peptidoglycan mesh unique to bacteria. Cell-wall synthesis and recycling are critical cellular processes essential for cell growth, elongation and division. Both de novo synthesis and recycling involve an array of enzymes across all cellular compartments, namely the outer membrane, periplasm, inner membrane and cytoplasm. Due to the exclusivity of peptidoglycan in the bacterial cell-wall, these players are the target of choice for many antibacterial agents. Our current understanding of cell-wall biochemistry and biogenesis in Gram-negative organisms stems mostly from studies of Escherichia coli. An incomplete knowledge on these processes exists for the opportunistic Gram-negative pathogen, Pseudomonas aeruginosa. In this review, cell-wall synthesis and recycling in the various cellular compartments are compared and contrasted between E. coli and P. aeruginosa. Despite the fact that there is a remarkable similarity of these processes between the two bacterial species, crucial differences alter their resistance to b-lactams, fluoroquinolones and aminoglycosides. One of the common mediators underlying resistance is the amp system whose mechanism of action is closely associated with the cell-wall recycling pathway. The activation of amp genes results in expression of AmpC blactamase through its cognate regulator AmpR which further regulates multi-drug resistance. In addition, other cell-wall recycling enzymes also contribute to antibiotic resistance. This comprehensive summary of the information should spawn new ideas on how to effectively target cell-wall processes to combat the growing resistance to existing antibiotics.

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“…In Pseudomonas aeruginosa, several works showed that AmpR is a global transcriptional regulator. It is a potential membrane-associated dimer that regulates genes involved in virulence, quorum sensing, and stress response (14)(15)(16)(17)(18). In addition, three AmpD enzymes have been found in P. aeruginosa.…”

mentioning

confidence: 99%

Complex Regulation Pathways of AmpC-Mediated β-Lactam Resistance in Enterobacter cloacae Complex

Guérin

Isnard

Cattoir

et al. 2015

Antimicrob Agents Chemother

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bEnterobacter cloacae complex (ECC), an opportunistic pathogen causing numerous infections in hospitalized patients worldwide, is able to resist ␤-lactams mainly by producing the AmpC ␤-lactamase enzyme. AmpC expression is highly inducible in the presence of some ␤-lactams, but the underlying genetic regulation, which is intricately linked to peptidoglycan recycling, is still poorly understood. In this study, we constructed different mutant strains that were affected in genes encoding enzymes suspected to be involved in this pathway. As expected, the inactivation of ampC, ampR (which encodes the regulator protein of ampC), and ampG (encoding a permease) abolished ␤-lactam resistance. Reverse transcription-quantitative PCR (qRT-PCR) experiments combined with phenotypic studies showed that cefotaxime (at high concentrations) and cefoxitin induced the expression of ampC in different ways: one involving NagZ (a N-acetyl-␤-D-glucosaminidase) and another independent of NagZ. Unlike the model established for Pseudomonas aeruginosa, inactivation of DacB (also known as PBP4) was not responsible for a constitutive ampC overexpression in ECC, whereas it caused AmpC-mediated high-level ␤-lactam resistance, suggesting a posttranscriptional regulation mechanism. Global transcriptomic analysis by transcriptome sequencing (RNA-seq) of a dacB deletion mutant confirmed these results. Lastly, analysis of 37 ECC clinical isolates showed that amino acid changes in the AmpD sequence were likely the most crucial event involved in the development of high-level ␤-lactam resistance in vivo as opposed to P. aeruginosa where dacB mutations have been commonly found. These findings bring new elements for a better understanding of ␤-lactam resistance in ECC, which is essential for the identification of novel potential drug targets.

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Structural and Functional Characterization of Pseudomonas aeruginosa Global Regulator AmpR

Cited by 40 publications

References 86 publications

RpoN Modulates Carbapenem Tolerance in Pseudomonas aeruginosa through Pseudomonas Quinolone Signal and PqsE

RpoN Modulates Carbapenem Tolerance in Pseudomonas aeruginosa through Pseudomonas Quinolone Signal and PqsE

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Complex Regulation Pathways of AmpC-Mediated β-Lactam Resistance in Enterobacter cloacae Complex

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