scholarly journals Novel roles for two-component regulatory systems in cytotoxicity and virulence-related properties in Pseudomonas aeruginosa

2018 ◽  
Vol 4 (1) ◽  
pp. 173-191 ◽  
Author(s):  
Shaan L. Gellatly ◽  
◽  
Manjeet Bains ◽  
Elena B.M. Breidenstein ◽  
Janine Strehmel ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Regulatory Systems ◽  
Two Component

scholarly journals Impact of Two-Component Regulatory Systems PhoP-PhoQ and PmrA-PmrB on Colistin Pharmacodynamics in Pseudomonas aeruginosa

2012 ◽  
Vol 56 (6) ◽  
pp. 3453-3456 ◽  
Author(s):  
Neang S. Ly ◽  
Jenny Yang ◽  
Jurgen B. Bulitta ◽  
Brian T. Tsuji
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pharmacodynamic Model ◽  
Maximal Effect ◽  
Wild Type ◽  
Content Type ◽  
Regulatory Systems ◽  
Two Component ◽  
Subinhibitory Concentrations

ABSTRACTThein vitropharmacodynamics of colistin againstPseudomonas aeruginosaPAO1 wild-type and isogenic knockout strains ofphoPandpmrAwere evaluated. Colistin killing at subinhibitory concentrations was greater against thephoPandpmrAmutants than the wild type within the first 8 h: the concentration that results in 50% of maximal effect (EC50) of thepmrAmutant (0.413 mg/liter) was less than that of the wild type (0.718 mg/liter) (P< 0.05). Anin vitropharmacodynamic model simulating human colistin regimens displayed initial killing followed by regrowth in thephoPmutant and gradual regrowth in thepmrAmutant and wild type.

scholarly journals SmeC, an Outer Membrane Multidrug Efflux Protein of Stenotrophomonas maltophilia

2002 ◽  
Vol 46 (2) ◽  
pp. 333-343 ◽  
Author(s):  
Xian-Zhi Li ◽  
Li Zhang ◽  
Keith Poole
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistance ◽  
Stenotrophomonas Maltophilia ◽  
Promoter Activity ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Regulatory Systems ◽  
Pcr Product ◽  
Two Component ◽  
Multidrug Efflux System

ABSTRACT A homologue of the mexAB-oprM multidrug efflux operon of Pseudomonas aeruginosa, smeABC, was cloned from Stenotrophomonas maltophilia by using, as a probe, a PCR product amplified from this organism with primers based on the mexB sequence. The smeABC genes were hyperexpressed in a mutant strain displaying resistance to several antimicrobials, including aminoglycosides, β-lactams, and fluoroquinolones. Deletions in smeC but not smeB compromised this resistance, suggesting that SmeC contributed to the multidrug resistance of the mutant as part of another, as-yet-unidentified multidrug efflux system. Consistent with SmeC functioning independently of SmeAB, a promoter activity was identified upstream of smeC. Upstream of the smeABC genes, a putative two-gene operon, smeSR, encoding homologues of bacterial two-component regulatory systems was identified. The cloned smeR gene activated expression of a smeA-lacZ fusion, indicating that SmeR positively regulates expression of the smeABC genes. Consistent with this, the multidrug resistance of the SmeABC-hyperexpressing mutant was compromised by deletion of smeR. Intriguingly, SmeC expression in S. maltophilia paralleled a β-lactamase activity provided by a C-terminally truncated L2 enzyme, which was apparently responsible for the β-lactam resistance of the SmeABC-hyperexpressing mutant. This represents the first report of coregulation of an efflux resistance determinant and a β-lactamase.

scholarly journals Contribution of the PhoP-PhoQ and PmrA-PmrB Two-Component Regulatory Systems to Mg2+-Induced Gene Regulation in Pseudomonas aeruginosa

2006 ◽  
Vol 188 (11) ◽  
pp. 3995-4006 ◽  
Author(s):  
Joseph B. McPhee ◽  
Manjeet Bains ◽  
Geoff Winsor ◽  
Shawn Lewenza ◽  
Agnieszka Kwasnicka ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Transcriptional Profiling ◽  
Polymyxin B ◽  
Dependent Manner ◽  
Binding Assays ◽  
Response Regulators ◽  
Binding Motifs ◽  
Regulatory Systems ◽  
Two Component ◽  
Genes Encoding

ABSTRACT When grown in divalent cation-limited medium, Pseudomonas aeruginosa becomes resistant to cationic antimicrobial peptides and polymyxin B. This resistance is regulated by the PhoP-PhoQ and PmrA-PmrB two-component regulatory systems. To further characterize Mg2+ regulation in P. aeruginosa, microarray transcriptional profiling was conducted to compare wild-type P. aeruginosa grown under Mg2+-limited and Mg2+-replete conditions to isogenic phoP and pmrA mutants grown under Mg2+-limited conditions. Under Mg2+-limited conditions (0.02 mM Mg2+), approximately 3% of the P. aeruginosa genes were differentially expressed compared to the expression in bacteria grown under Mg2+-replete conditions (2 mM Mg2+). Only a modest subset of the Mg2+-regulated genes were regulated through either PhoP or PmrA. To determine which genes were directly regulated, a bioinformatic search for conserved binding motifs was combined with confirmatory reverse transcriptase PCR and gel shift promoter binding assays, and the results indicated that very few genes were directly regulated by these response regulators. It was found that in addition to the previously known oprH-phoP-phoQ operon and the pmrHFIJKLM-ugd operon, the PA0921 and PA1343 genes, encoding small basic proteins, were regulated by Mg2+ in a PhoP-dependent manner. The number of known PmrA-regulated genes was expanded to include the PA1559-PA1560, PA4782-PA4781, and feoAB operons, in addition to the previously known PA4773-PA4775-pmrAB and pmrHFIJKLM-ugd operons.

scholarly journals The Pseudomonas aeruginosa CreBC Two-Component System Plays a Major Role in the Response to β-Lactams, Fitness, Biofilm Growth, and Global Regulation

2014 ◽  
Vol 58 (9) ◽  
pp. 5084-5095 ◽  
Author(s):  
Laura Zamorano ◽  
Bartolomé Moyà ◽  
Carlos Juan ◽  
Xavier Mulet ◽  
Jesús Blázquez ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Anaerobic Respiration ◽  
Biofilm Growth ◽  
Content Type ◽  
Comprehensive Collection ◽  
Regulatory Systems ◽  
Two Component ◽  
Life Threatening ◽  
Inner Membrane Protein ◽  
Biofilm Development

ABSTRACTPseudomonas aeruginosais a ubiquitous versatile environmental microorganism with a remarkable ability to grow under diverse environmental conditions. Moreover,P. aeruginosais responsible for life-threatening infections in immunocompromised and cystic fibrosis patients, as the extraordinary capacity of this pathogen to develop antimicrobial resistance dramatically limits our therapeutic arsenal. Its large genome carries an outstanding number of genes belonging to regulatory systems, including multiple two-component sensor-regulator systems that modulate the response to the different environmental stimuli. Here, we show that one of two systems, designated CreBC (carbon source responsive) and BlrAB (β-lactam resistance), might be of particular relevance. We first identified the stimuli triggering the activation of the CreBC system, which specifically responds to penicillin-binding protein 4 (PBP4) inhibition by certain β-lactam antibiotics. Second, through an analysis of a large comprehensive collection of mutants, we demonstrate an intricate interconnection between the CreBC system, the peptidoglycan recycling pathway, and the expression of the concerning chromosomal β-lactamase AmpC. Third, we show that the CreBC system, and particularly its effector inner membrane protein CreD, plays a major role in bacterial fitness and biofilm development, especially in the presence of subinhibitory concentrations of β-lactams. Finally, global transcriptomics reveals broad regulatory functions of CreBC in basic physiological aspects, particularly anaerobic respiration, in both the presence and absence of antibiotics. Therefore, the CreBC system is envisaged as a potentially interesting target for improving the efficacy of β-lactams againstP. aeruginosainfections.

scholarly journals Alterations in Two-Component Regulatory Systems of phoPQ and pmrAB Are Associated with Polymyxin B Resistance in Clinical Isolates of Pseudomonas aeruginosa

2009 ◽  
Vol 53 (12) ◽  
pp. 5150-5154 ◽  
Author(s):  
Kaddy Barrow ◽  
Dong H. Kwon
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Amino Acid ◽  
Polymyxin B ◽  
Clinical Isolates ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Strain Pao1 ◽  
Truncated Protein ◽  
Regulatory Systems ◽  
Two Component

ABSTRACT Polymyxins are often the only option to treat acquired multidrug-resistant Pseudomonas aeruginosa. Polymyxin susceptibility in P. aeruginosa PAO1 is associated with the lipopolysaccharide structure that is determined by arnBCADTEF and modulated by phoPQ and pmrAB. We examined five clonally unrelated clinical isolates of polymyxin B-resistant P. aeruginosa to investigate the molecular basis of polymyxin resistance. All isolates grew with 4 μg/ml polymyxin B (MIC, 8 μg/ml), whereas P. aeruginosa PAO1 grew with 0.25 μg/ml polymyxin B (MIC, 0.5 μg/ml). The resistant isolates were converted to susceptible ones (the MICs fell from 8 to 0.5 μg/ml) following the introduction of phoPQ (four isolates) and pmrAB (one isolate), which had been cloned from strain PAO1. DNA sequence analysis revealed that a single-nucleotide substitution in three isolates replaced a single amino acid of PhoQ, the deletion of 17 nucleotides in one isolate truncated the protein of PhoQ, and two nucleotide substitutions in one isolate replaced two amino acids of PmrB. The involvement of these amino acid substitutions or the truncated protein of PhoQ and PmrB in polymyxin B resistance was confirmed using strain PAO1 lacking phoPQ or pmrAB that was transformed by phoPQ or pmrAB containing the amino acid substitutions or the truncated protein. The resistant clinical isolates were sensitized by the inactivation of arnBCADTEF (the MICs fell from 8 to 0.5 μg/ml). These results suggest that polymyxin B resistance among clinical isolates of P. aeruginosa is associated with alterations in two-component regulatory systems of phoPQ or pmrAB.

scholarly journals The Pseudomonas aeruginosa PhoP-PhoQ Two-Component Regulatory System Is Induced upon Interaction with Epithelial Cells and Controls Cytotoxicity and Inflammation

2012 ◽  
Vol 80 (9) ◽  
pp. 3122-3131 ◽  
Author(s):  
Shaan L. Gellatly ◽  
Brittany Needham ◽  
Laurence Madera ◽  
M. Stephen Trent ◽  
Robert E. W. Hancock
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Lipid A ◽  
Regulatory System ◽  
Dependent Manner ◽  
Wild Type ◽  
Content Type ◽  
Regulatory Systems ◽  
Two Component ◽  
Inflammatory Phenotype

ABSTRACTThe adaptation ofPseudomonas aeruginosato its environment, including the host, is tightly controlled by its network of regulatory systems. The two-component regulatory system PhoPQ has been shown to play a role in the virulence and polymyxin resistance ofP. aeruginosaas well as several other Gram-negative species. Dysregulation of this system has been demonstrated in clinical isolates, yet how it affects virulence ofP. aeruginosais unknown. To investigate this, an assay was used whereby bacteria were cocultured with human bronchial epithelial cells. The interaction of wild-type (WT) bacteria that had adhered to epithelial cells led to a large upregulation of the expression of theoprH-phoP-phoQoperon and its target, thearnlipopolysaccharide (LPS) modification operon, in a PhoQ-dependent manner, compared to cells in the supernatant that had failed to adhere. Relative to the wild type, aphoQmutant cocultured on epithelial cells produced less secreted protease and lipase and, like thephoQmutant,piv,lipH, andlasBmutants demonstrated reduced cytotoxicity toward epithelial cells. Mutation inphoQalso resulted in alterations to lipid A and to increased inflammatory LPS. These data indicate that mutation ofphoQresults in a phenotype that is similar to the less virulent but more inflammatory phenotype of clinical strains isolated from chronic-stage cystic fibrosis lung infections.

scholarly journals Two-component regulatory systems in Pseudomonas aeruginosa: an intricate network mediating fimbrial and efflux pump gene expression

2011 ◽  
Vol 79 (5) ◽  
pp. 1353-1366 ◽  
Author(s):  
Melissa Sivaneson ◽  
Helga Mikkelsen ◽  
Isabelle Ventre ◽  
Christophe Bordi ◽  
Alain Filloux
Keyword(s):  
Gene Expression ◽  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Regulatory Systems ◽  
Two Component
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