The CpxR/CpxA Two-component Regulatory System Up-regulates the Multidrug Resistance Cascade to Facilitate Escherichia coli Resistance to a Model Antimicrobial Peptide

Weatherspoon-Griffin, Natasha; Yang, Dezhi; Kong, Wei; Hua, Zichun; Shi, Yixin

doi:10.1074/jbc.m114.565762

Cited by 102 publications

(60 citation statements)

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“…OmpR in E. coli reciprocally regulates ompF and ompC depending on the osmotic conditions of the environment (56). CpxR in E. coli promotes expression of marR and represses expression of ung (57,58). CvsR appears to be similar in its ability to promote and repress expression of different genes.…”

Section: Discussionmentioning

confidence: 99%

Ca ²⁺ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000

et al. 2018

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Two-component systems (TCSs) of bacteria regulate many different aspects of the bacterial life cycle, including pathogenesis. Most TCSs remain uncharacterized, with no information about the signal(s) or regulatory targets and/or role in bacterial pathogenesis. Here, we characterized a TCS in the plant-pathogenic bacterium Pseudomonas syringae pv. tomato DC3000 composed of the histidine kinase CvsS and the response regulator CvsR. CvsSR is necessary for virulence of P. syringae pv. tomato DC3000, since ΔcvsS and ΔcvsR strains produced fewer symptoms than the wild type (WT) and demonstrated reduced growth on multiple hosts. We discovered that expression of cvsSR is induced by Ca 2ϩ concentrations found in leaf apoplastic fluid. Thus, Ca 2ϩ can be added to the list of signals that promote pathogenesis of P. syringae pv. tomato DC3000 during host colonization. Through chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) and global transcriptome analysis (RNA-seq), we discerned the CvsR regulon. CvsR directly activated expression of the type III secretion system regulators, hrpR and hrpS, that regulate P. syringae pv. tomato DC3000 virulence in a type III secretion system-dependent manner. CvsR also indirectly repressed transcription of the extracytoplasmic sigma factor algU and production of alginate. Phenotypic analysis determined that CvsSR inversely regulated biofilm formation, swarming motility, and cellulose production in a Ca 2ϩ -dependent manner. Overall, our results show that CvsSR is a key regulatory hub critical for interaction with host plants. IMPORTANCE Pathogenic bacteria must be able to react and respond to the surrounding environment, make use of available resources, and avert or counter host immune responses. Often, these abilities rely on two-component systems (TCSs) composed of interacting proteins that modulate gene expression. We identified a TCS in the plant-pathogenic bacterium Pseudomonas syringae that responds to the presence of calcium, which is an important signal during the plant defense response. We showed that when P. syringae is grown in the presence of calcium, this TCS regulates expression of factors contributing to disease. Overall, our results provide a better understanding of how bacterial pathogens respond to plant signals and control systems necessary for eliciting disease.KEYWORDS Pseudomonas syringae, alginate, biofilms, calcium signaling, two-component regulatory systems P seudomonas syringae is a hemibiotrophic plant-pathogenic bacterial species composed of approximately 50 pathovars that differ in their host range (1, 2). This species causes significant economic losses to a number of crops, with certain pathovars being responsible for severe outbreaks of disease worldwide. Recent outbreaks include bleeding canker disease on horse chestnut caused by P. syringae pv. aesculi and

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Section: Discussionmentioning

confidence: 99%

Ca ²⁺ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000

et al. 2018

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“…A 2CSTS that acts upon the transcription of tier III genes is CpxA/CpxR. This 2CSTS responds to envelope stress, inhibits LEE gene transcription (82), and activates the synthesis pathway that leads to the production of an antimicrobial peptide that causes multidrug resistance (83). Direct binding of CpxR-P to the promoter regions of the motA and tsr operons has been shown (84) and so has transcriptional repression of csgD by CpxR (33,85).…”

Section: Additional Downstream Regulation Of Flagellar Genesmentioning

confidence: 99%

Involvement of Two-Component Signaling on Bacterial Motility and Biofilm Development

Prüß

2017

J Bacteriol

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Two-component signaling is a specialized mechanism that bacteria use to respond to changes in their environment. Nonpathogenic strains of Escherichia coli K-12 harbor 30 histidine kinases and 32 response regulators, which form a network of regulation that integrates many other global regulators that do not follow the two-component signaling mechanism, as well as signals from central metabolism. The output of this network is a multitude of phenotypic changes in response to changes in the environment. Among these phenotypic changes, many twocomponent systems control motility and/or the formation of biofilm, sessile communities of bacteria that form on surfaces. Motility is the first reversible attachment phase of biofilm development, followed by a so-called swim or stick switch toward surface organelles that aid in the subsequent phases. In the mature biofilm, motility heterogeneity is generated by a combination of evolutionary and gene regulatory events.

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“…Strain A5-1 had a 6,115-bp deletion including marRAB (ydeA, marRAB, eamA, and ydeEH). Regulators of Mar showed point mutations in strain G5-2 (mar paralog rob [26]) and in strain A1-1 (two-component activator cpxA [59]). Additional mutations appeared in other multidrug efflux systems: emrA and emrY (32,60), mdtA and deletions covering mdtEF (60), and yeaS (leuE) leucine export (61).…”

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confidence: 99%

Benzoate- and Salicylate-Tolerant Strains of Escherichia coli K-12 Lose Antibiotic Resistance during Laboratory Evolution

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et al. 2017

Appl Environ Microbiol

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Escherichia coli K-12 W3110 grows in the presence of membrane-permeant organic acids that can depress cytoplasmic pH and accumulate in the cytoplasm. We conducted experimental evolution by daily diluting cultures in increasing concentrations of benzoic acid (up to 20 mM) buffered at external pH 6.5, a pH at which permeant acids concentrate in the cytoplasm. By 2,000 generations, clones isolated from evolving populations showed increasing tolerance to benzoate but were sensitive to chloramphenicol and tetracycline. Sixteen clones grew to stationary phase in 20 mM benzoate, whereas the ancestral strain W3110 peaked and declined. Similar growth occurred in 10 mM salicylate. Benzoate-evolved strains grew like W3110 in the absence of benzoate, in media buffered at pH 4.8, pH 7.0, or pH 9.0, or in 20 mM acetate or sorbate at pH 6.5. Genomes of 16 strains revealed over 100 mutations, including single-nucleotide polymorphisms (SNPs), large deletions, and insertion knockouts. Most strains acquired deletions in the benzoate-induced multiple antibiotic resistance (Mar) regulon or in associated regulators such as rob and cpxA, as well as the multidrug resistance (MDR) efflux pumps emrA, emrY, and mdtA. Strains also lost or downregulated the Gad acid fitness regulon. In 5 mM benzoate or in 2 mM salicylate (2-hydroxybenzoate), most strains showed increased sensitivity to the antibiotics chloramphenicol and tetracycline; some strains were more sensitive than a marA knockout strain. Thus, our benzoate-evolved strains may reveal additional unknown drug resistance components. Benzoate or salicylate selection pressure may cause general loss of MDR genes and regulators. IMPORTANCE Benzoate is a common food preservative, and salicylate is the primary active metabolite of aspirin. In the gut microbiome, genetic adaptation to salicylate may involve loss or downregulation of inducible multidrug resistance systems. This discovery implies that aspirin therapy may modulate the human gut microbiome to favor salicylate tolerance at the expense of drug resistance. Similar aspirin-associated loss of drug resistance might occur in bacterial pathogens found in arterial plaques.

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The CpxR/CpxA Two-component Regulatory System Up-regulates the Multidrug Resistance Cascade to Facilitate Escherichia coli Resistance to a Model Antimicrobial Peptide

Cited by 102 publications

References 46 publications

Ca ²⁺ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000

Ca ²⁺ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000

Involvement of Two-Component Signaling on Bacterial Motility and Biofilm Development

Benzoate- and Salicylate-Tolerant Strains of Escherichia coli K-12 Lose Antibiotic Resistance during Laboratory Evolution

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The CpxR/CpxA Two-component Regulatory System Up-regulates the Multidrug Resistance Cascade to Facilitate Escherichia coli Resistance to a Model Antimicrobial Peptide

Cited by 102 publications

References 46 publications

Ca 2+ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000

Ca 2+ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000

Involvement of Two-Component Signaling on Bacterial Motility and Biofilm Development

Benzoate- and Salicylate-Tolerant Strains of Escherichia coli K-12 Lose Antibiotic Resistance during Laboratory Evolution

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Ca ²⁺ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000

Ca ²⁺ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000