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PMID:22479525

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Citation

Balasubramanian, D, Schneper, L, Merighi, M, Smith, R, Narasimhan, G, Lory, S and Mathee, K (2012) The regulatory repertoire of Pseudomonas aeruginosa AmpC ß-lactamase regulator AmpR includes virulence genes. PLoS ONE 7:e34067

Abstract

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, PAOΔampR. 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.

Links

PubMed PMC3315558 Online version:10.1371/journal.pone.0034067

Keywords

Animals; Anti-Bacterial Agents/pharmacology; Bacterial Proteins/genetics; Bacterial Proteins/physiology; Biofilms; Caenorhabditis elegans; Drug Resistance, Bacterial; Gene Deletion; Gene Expression Regulation, Bacterial; Gene Transfer, Horizontal; Mutation; Oligonucleotide Array Sequence Analysis; Phenotype; Polymerase Chain Reaction/methods; Pseudomonas aeruginosa/genetics; Pseudomonas aeruginosa/pathogenicity; Transcriptome; Virulence; Virulence Factors/metabolism; beta-Lactamases/genetics; beta-Lactamases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

PSEAE:AMPR

involved_in

GO:1900378: positive regulation of secondary metabolite biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

PSEAE:AMPR

involved_in

GO:1900232: negative regulation of single-species biofilm formation on inanimate substrate

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

PSEAE:AMPR

involved_in

GO:0050714: positive regulation of protein secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

PSEAE:AMPR

involved_in

GO:0045862: positive regulation of proteolysis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

PSEAE:AMPR

involved_in

GO:0006355: regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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