Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Mar;73(2):1-14.
doi: 10.1111/2049-632X.12208. Epub 2015 Feb 26.

Pseudomonas Aeruginosa AmpR: An Acute-Chronic Switch Regulator

Affiliations
Free PMC article
Review

Pseudomonas Aeruginosa AmpR: An Acute-Chronic Switch Regulator

Deepak Balasubramanian et al. Pathog Dis. .
Free PMC article

Abstract

Pseudomonas aeruginosa is one of the most intractable human pathogens that pose serious clinical challenge due to extensive prevalence of multidrug-resistant clinical isolates. Armed with abundant virulence and antibiotic resistance mechanisms, it is a major etiologic agent in a number of acute and chronic infections. A complex and intricate network of regulators dictates the expression of pathogenicity factors in P. aeruginosa. Some proteins within the network play key roles and control multiple pathways. This review discusses the role of one such protein, AmpR, which was initially recognized for its role in antibiotic resistance by regulating AmpC β-lactamase. Recent genomic, proteomic and phenotypic analyses demonstrate that AmpR regulates expression of hundreds of genes that are involved in diverse pathways such as β-lactam and non-β-lactam resistance, quorum sensing and associated virulence phenotypes, protein phosphorylation, and physiological processes. Finally, ampR mutations in clinical isolates are reviewed to shed light on important residues required for its function in antibiotic resistance. The prevalence and evolutionary implications of AmpR in pathogenic and nonpathogenic proteobacteria are also discussed. A comprehensive understanding of proteins at nodal positions in the P. aeruginosa regulatory network is crucial in understanding, and ultimately targeting, the pathogenic stratagems of this organism.

Keywords: Pseudomonas aeruginosa virulence; antibiotic resistance; c-di-GMP; global regulator; quorum sensing; ser/thr protein phosphorylation.

Figures

None
This is a timely and well-written review summarizing recent findings on the role of the global regulator AmpR on Pseudomonas aeruginosa virulence and physiology. The significance of this regulator has broadened from its established role in regulation of beta-lactam resistance to novel, unexpected, multiple regulatory functions including the switch between acute and chronic modes of infection.
Figure 1.
Figure 1.
Genetic locus of the ampR-ampC module. The open reading frames and operons surrounding ampR-ampC in Pseudomonas aeruginosa and different enterobacterial species are shown. The presence of a divergently transcribed ampR (P. aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens) indicates inducible β-lactamase production, whereas in Escherichia coli and Shigella sonnei, ampC expression is constitutively low.
Figure 2.
Figure 2.
Pseudomonas aeruginosa AmpR sequence homology. The P. aeruginosa AmpR sequence from the Pseudomonas Database (Winsor et al., 2011) was used to determine similarity with its homologs in two other Enterobacteriaceae members using clustalw2. Mutations in the P. aeruginosa AmpR sequence identified in antibiotic-resistant clinical isolates are shown in red. The arrows indicate the mutations confirmed in the laboratory that contribute to enhanced resistance.
Figure 3.
Figure 3.
AmpR is a global regulator in Pseudomonas aeruginosa. AmpR regulates resistance to different classes of clinically relevant antibiotics, either positively (β-lactams, aminoglycosides) or negatively (quinolones). AmpR plays a key role in determining P. aeruginosa virulence and physiology by regulating expression of transcriptional and post-transcriptional regulators that feed into critical networks, such as QS, Gac-Rsm, iron uptake, and stress response pathways. The data in the figure were obtained from gene expression/proteomic/phenotypic assays (Balasubramanian et al., , ; Kumari et al., 2014a,b). Only the gene expression confirmed by qPCR and/or phenotypes confirmed by assays are shown here. Arrow colors indicate positive (green) and negative (red) regulation. No distinction has been made between direct and indirect regulations. AmpR model based on the Protein Model Portal (Tacconelli et al., 2014) is shown in the center. The model shows the DNA-binding helix-turn-helix motif (blue), a hydrophobic domain (green), and the C-terminal effector-binding domain (yellow and cyan).
Figure 4.
Figure 4.
Prevalence and relatedness of AmpR in proteobacteria. The precomputed blast data for the AmpR (PA4109) amino acid sequence from the Pseudomonas Genome Database (Winsor et al., 2011) were used to identify homologs in other bacteria. The cutoff score was set at 850 corresponding to 56% protein identity. For the sake of clarity, only the top hit identified in the sequenced genomes of each species was considered for further analysis. The matches that conform to these criteria were aligned using NCBI Constraint-Based Multiple Alignment Tool (Papadopoulos and Agarwala 2007), and the resulting alignment file was used to generate a phylogenetic tree (Dereeper et al., 2008, 2010). The GI protein IDs in the Newick format of the tree were replaced with organism names (identified using the NCBI Batch Entrez), and the tree was visualized using the Interactive Tree of Life (Letunic and Bork 2007, 2011).

Similar articles

See all similar articles

Cited by 20 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback