The Two-Component System CprRS Senses Cationic Peptides and Triggers Adaptive Resistance in Pseudomonas aeruginosa Independently of ParRS

Fernández, Lucía; Jenssen, Håvard; Bains, Manjeet; Wiegand, Irith; Gooderham, W. James; Hancock, Robert E. W.

doi:10.1128/aac.01530-12

Cited by 121 publications

(132 citation statements)

References 40 publications

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“…Compared to P. aeruginosa wild-type biofilms, ⌬brlR mutant biofilms were characterized by a 5.4-fold increase in arnC transcript abundance, while overexpression of brlR correlated with decreased arnC expression, as determined using qRT-PCR (Table 3). In P. aeruginosa, four TCS have been shown to act upon the arn operon, namely, ParRS and CprRS, which are activated upon sensing antimicrobial peptides, and PmrAB and PhoPQ, which respond to limiting extracellular concentrations of divalent Mg 2ϩ and Ca 2ϩ (25)(26)(27)(28)(29). qRT-PCR confirmed that inactivation of brlR correlates with increased phoP and phoQ expression compared to wild-type biofilms, while decreased phoP and phoQ transcript abundance was detected in biofilms overexpressing brlR (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…In P. aeruginosa, activation of arnBCADTEF expression has been linked to two separate twocomponent regulatory systems, PhoPQ and PmrAB, which respond to limiting extracellular concentrations of divalent Mg 2ϩ and Ca 2ϩ (25)(26)(27). In contrast, peptide-mediated adaptive resistance requires the two-component systems (TCS) ParRS and CprRS, which lead to activation of the LPS modification system upon exposure to a wide range of antimicrobial peptides (28,29).…”

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confidence: 99%

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The MerR-Like Regulator BrlR Impairs Pseudomonas aeruginosa Biofilm Tolerance to Colistin by Repressing PhoPQ

Chambers

Sauer

2013

J Bacteriol

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While the MerR-like transcriptional regulator BrlR has been demonstrated to contribute to Pseudomonas aeruginosa biofilm tolerance to antimicrobial agents known as multidrug efflux pump substrates, the role of BrlR in resistance to cationic antimicrobial peptides (CAP), which is based on reduced outer membrane susceptibility, is not known. Here, we demonstrate that inactivation of brlR coincided with increased resistance of P. aeruginosa to colistin, while overexpression of brlR resulted in increased susceptibility. brlR expression correlated with reduced transcript abundances of phoP, phoQ, pmrA, pmrB, and arnC. Inactivation of pmrA and pmrB had no effect on the susceptibility of P. aeruginosa biofilms to colistin, while inactivation of phoP and phoQ rendered biofilms more susceptible than the wild type. The susceptibility phenotype of ⌬phoP biofilms to colistin was comparable to that of P. aeruginosa biofilms overexpressing brlR. BrlR was found to directly bind to oprH promoter DNA of the oprH-phoPQ operon. BrlR reciprocally contributed to colistin and tobramycin resistance in P. aeruginosa PAO1 and CF clinical isolates, with overexpression of brlR resulting in increased tobramycin MICs and increased tobramycin resistance but decreased colistin MICs and increased colistin susceptibility. The opposite trend was observed upon brlR inactivation. The difference in susceptibility to colistin and tobramycin was eliminated by combination treatment of biofilms with both antibiotics. Our findings establish BrlR as an unusual member of the MerR family, as it not only functions as a multidrug transport activator, but also acts as a repressor of phoPQ expression, thus suppressing colistin resistance.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

The MerR-Like Regulator BrlR Impairs Pseudomonas aeruginosa Biofilm Tolerance to Colistin by Repressing PhoPQ

Chambers

Sauer

2013

J Bacteriol

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“…A third regulator, ParRS, has also been shown to be involved in adaptive resistance to polymyxins (18). More recently, two additional regulators (ColRS and CprRS) that are essential for PhoPQmediated peptide resistance have been identified (20,25). Adding to the complexity, ColRS and CprRS also appear to regulate polymyxin resistance outside of 4-amino-L-arabinose modification of lipid A.…”

Section: Discussionmentioning

confidence: 99%

Irreproducible and Uninterpretable Polymyxin B MICs for Enterobacter cloacae and Enterobacter aerogenes

2013

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Carbapenem-resistant Enterobacter species are emerging nosocomial pathogens. As with most multidrug-resistant Gram-negative pathogens, the polymyxins are often the only therapeutic option. In this study involving clinical isolates of E. cloacae and E. aerogenes, susceptibility testing methods with polymyxin B were analyzed. All isolates underwent testing by the broth microdilution (in duplicate) and agar dilution (in duplicate) methods, and select isolates were examined by the Etest method. Selected isolates were also examined for heteroresistance by population analysis profiling. Using a susceptibility breakpoint of <2 g/ml, categorical agreement by all four dilution tests (two broth microdilution and two agar dilution) was achieved in only 76/114 (67%) of E. cloacae isolates (65 susceptible, 11 resistant). Thirty-eight (33%) had either conflicting or uninterpretable results (multiple skip wells, i.e., wells that exhibit no growth although growth does occur at higher concentrations). Of the 11 consistently resistant isolates, five had susceptible MICs as determined by Etest. Heteroresistant subpopulations were detected in eight of eight isolates tested, with greater percentages in isolates with uninterpretable MICs. For E. aerogenes, categorical agreement between the four dilution tests was obtained in 48/56 (86%), with conflicting and/or uninterpretable results in 8/56 (14%). For polymyxin susceptibility testing of Enterobacter species, close attention must be paid to the presence of multiple skip wells, leading to uninterpretable results. Susceptibility also should not be assumed based on the results of a single test. Until the clinical relevance of skip wells is defined, interpretation of polymyxin susceptibility tests for Enterobacter species should be undertaken with extreme caution.

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“…P. aeruginosa ColS shares 76% similarity with that of P. fluorescens, while the ColR homologues are 91% similar (29). PA3078 encodes a sensor kinase, and the upstream locus PA3077 encodes the cognate response regulator; these were recently designated cprS and cprR, respectively (48). P. aeruginosa CprS is 45% similar to ColS of P. fluorescens, while CprR is 68% similar to ColR of P. fluorescens.…”

Section: Transposon Insertion In Pa4381 (Colr) Pa3078 (Cprs) or 39mentioning

confidence: 99%

“…P. aeruginosa CprS is 45% similar to ColS of P. fluorescens, while CprR is 68% similar to ColR of P. fluorescens. In addition, the transposon analysis identified PA1559, encoding a hypothetical protein; the CprRS system was previously shown to regulate this locus (48).…”

Section: Transposon Insertion In Pa4381 (Colr) Pa3078 (Cprs) or 39mentioning

confidence: 99%

Polymyxin Resistance of Pseudomonas aeruginosa phoQ Mutants Is Dependent on Additional Two-Component Regulatory Systems

Gutu

Sgambati

Strasbourger

et al. 2013

Antimicrob Agents Chemother

107

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e Pseudomonas aeruginosa can develop resistance to polymyxin as a consequence of mutations in the PhoPQ regulatory system, mediated by covalent lipid A modification. Transposon mutagenesis of a polymyxin-resistant phoQ mutant defined 41 novel loci required for resistance, including two regulatory systems, ColRS and CprRS. Deletion of the colRS genes, individually or in tandem, abrogated the polymyxin resistance of a ⌬phoQ mutant, as did individual or tandem deletion of cprRS. Individual deletion of colR or colS in a ⌬phoQ mutant also suppressed 4-amino-L-arabinose addition to lipid A, consistent with the known role of this modification in polymyxin resistance. Surprisingly, tandem deletion of colRS or cprRS in the ⌬phoQ mutant or individual deletion of cprR or cprS failed to suppress 4-amino-L-arabinose addition to lipid A, indicating that this modification alone is not sufficient for PhoPQ-mediated polymyxin resistance in P. aeruginosa. Episomal expression of colRS or cprRS in tandem or of cprR individually complemented the Pm resistance phenotype in the ⌬phoQ mutant, while episomal expression of colR, colS, or cprS individually did not. Highly polymyxin-resistant phoQ mutants of P. aeruginosa isolated from polymyxin-treated cystic fibrosis patients harbored mutant alleles of colRS and cprS; when expressed in a ⌬phoQ background, these mutant alleles enhanced polymyxin resistance. These results define ColRS and CprRS as two-component systems regulating polymyxin resistance in P. aeruginosa, indicate that addition of 4-amino-L-arabinose to lipid A is not the only PhoPQ-regulated biochemical mechanism required for resistance, and demonstrate that colRS and cprS mutations can contribute to high-level clinical resistance.

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The Two-Component System CprRS Senses Cationic Peptides and Triggers Adaptive Resistance in Pseudomonas aeruginosa Independently of ParRS

Cited by 121 publications

References 40 publications

The MerR-Like Regulator BrlR Impairs Pseudomonas aeruginosa Biofilm Tolerance to Colistin by Repressing PhoPQ

The MerR-Like Regulator BrlR Impairs Pseudomonas aeruginosa Biofilm Tolerance to Colistin by Repressing PhoPQ

Irreproducible and Uninterpretable Polymyxin B MICs for Enterobacter cloacae and Enterobacter aerogenes

Polymyxin Resistance of Pseudomonas aeruginosa phoQ Mutants Is Dependent on Additional Two-Component Regulatory Systems

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