The contribution of PmrAB to the virulence of a clinical isolate of<i>Escherichia coli</i>

Warner, Douglas M.; Duval, Valérie; Levy, Stuart B.

doi:10.4161/viru.25931

Cited by 7 publications

(7 citation statements)

References 24 publications

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“…This process contributed to the bacterium’s survival in both host and non-host environments ( Gunn, 2008 ). In E. coli , pmrAB has been also reported to influence the cell’s resistance to antimicrobial peptides, toxic levels of iron, deoxycholate, and contributes to virulence ( Warner et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic and biophysical characterization of polymyxin resistance response regulator PmrA in Acinetobacter baumannii

Ouyang,

He,

Jiao

et al. 2024

Front. Microbiol.

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IntroductionAcinetobacter baumannii PmrAB is a crucial two-component regulatory system (TCS) that plays a vital role in conferring resistance to polymyxin. PmrA, a response regulator belonging to the OmpR/PhoB family, is composed of a C-terminal DNA-binding effector domain and an N-terminal receiver domain. The receiver domain can be phosphorylated by PmrB, a transmembrane sensor histidine kinase that interacts with PmrA. Once phosphorylated, PmrA undergoes a conformational change, resulting in the formation of a symmetric dimer in the receiver domain. This conformational change facilitates the recognition of promoter DNA by the DNA-binding domain of PmrA, leading to the activation of adaptive responses.MethodsX-ray crystallography was carried out to solve the structure of PmrA receiver domain. Electrophoretic mobility shift assay and Isothermal titration calorimetry were recruited to validate the interaction between the recombinant PmrA protein and target DNA. Field-emission scanning electron microscopy (FE-SEM) was employed to characterize the surface morphology of A. baumannii in both the PmrA knockout and mutation strains.ResultsThe receiver domain of PmrA follows the canonical α5β5 response regulator assembly, which undergoes dimerization upon phosphorylation and activation. Beryllium trifluoride is utilized as an aspartate phosphorylation mimic in this process. Mutations involved in phosphorylation and dimerization significantly affected the expression of downstream pmrC and naxD genes. This impact resulted in an enhanced cell surface smoothness with fewer modifications, ultimately contributing to a decrease in colistin (polymyxin E) and polymyxin B resistance. Additionally, a conservative direct-repeat DNA PmrA binding sequence TTTAAGNNNNNTTTAAG was identified at the promoter region of the pmrC and naxD gene. These findings provide structural insights into the PmrA receiver domain and reveal the mechanism of polymyxin resistance, suggesting that PmrA could be a potential drug target to reverse polymyxin resistance in Acinetobacter baumannii.

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Section: Discussionmentioning

confidence: 99%

Mechanistic and biophysical characterization of polymyxin resistance response regulator PmrA in Acinetobacter baumannii

Ouyang,

He,

Jiao

et al. 2024

Front. Microbiol.

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“…This study provides insights into the molecular mechanisms of colistin resistance in A. baumannii in harsh environmental conditions such as acidic pH. As PmrAB also regulates virulence determinants responsible for pathogenicity [30][31][32], the complex regulatory network of A. baumannii in response to different environmental factors should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Acinetobacter baumannii under Acidic Conditions Induces Colistin Resistance through PmrAB Activation and Lipid A Modification

Kim

Park

et al. 2023

Antibiotics

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Colistin is a last-resort antimicrobial agent for treating carbapenem-resistant Acinetobacter baumannii infections. The activation of PmrAB by several environmental signals induces colistin resistance in Gram-negative bacteria. This study investigated the molecular mechanisms of colistin resistance in A. baumannii under acidic conditions using wild-type (WT) A. baumannii 17978, ΔpmrA and ΔpmrB mutants, and pmrA-complemented strains. The pmrA or pmrB deletion did not affect the growth of A. baumannii under acidic or aerobic conditions. A. baumannii under acidic (pH 5.5) and high-iron (1 mM) conditions showed 32- and 8-fold increases in the minimum inhibitory concentrations (MICs) of colistin, respectively. The ΔpmrA and ΔpmrB mutants at pH 5.5 showed a significant decrease in colistin MICs compared to the WT strain at pH 5.5. No difference in colistin MICs was observed between WT and mutant strains under high-iron conditions. The pmrCAB expression significantly increased in the WT strain at pH 5.5 compared to the WT strain at pH 7.0. The pmrC expression significantly decreased in two mutant strains at pH 5.5 compared to the WT strain at pH 5.5. The PmrA protein was expressed in the ΔpmrA strain carrying ppmrA_FLAG plasmids at pH 5.5 but not at pH 7.0. Lipid A modification by the addition of phosphoethanolamine was observed in the WT strain at pH 5.5. In conclusion, this study demonstrated that A. baumannii under acidic conditions induces colistin resistance via the activation of pmrCAB operon and subsequent lipid A modification.

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“…This polymyxinlipid A interaction leads to destabilization of the LPS layer and reduces bacterial outer membrane integrity (18), although the exact mode of killing by colistin is currently unknown. Polymyxin resistance via pEtN addition to lipid A by pEtN transferases has been characterized in several organisms, including E. coli and species within the genera Neisseria and Campylobacter (19)(20)(21). This modification leads to polymyxin resistance, as it results in a change to the overall charge of the lipid A (22); colistin-resistant strains of A. baumannii have a reduced negative membrane charge compared to colistinsensitive strains (23).…”

Section: Discussionmentioning

confidence: 99%

Emergence of High-Level Colistin Resistance in an Acinetobacter baumannii Clinical Isolate Mediated by Inactivation of the Global Regulator H-NS

Lucas

Crane

Wright

et al. 2018

Antimicrob Agents Chemother

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Colistin is a crucial last-line drug used for the treatment of life-threatening infections caused by multidrug-resistant strains of the Gram-negative bacterium However, colistin-resistant isolates can still be isolated following failed colistin therapy. Resistance is most often mediated by the addition of phosphoethanolamine (pEtN) to lipid A by PmrC, following missense mutations in the operon encoding PmrC and the two-component signal transduction system PmrA/PmrB. We recovered a pair of isolates from a single patient before (6009-1) and after (6009-2) failed colistin treatment. These strains displayed low and very high levels of colistin resistance (MICs, 8 to 16 μg/ml and 128 μg/ml), respectively. To understand how increased colistin resistance arose, we sequenced the genome of each isolate, which revealed that 6009-2 had an extra copy of the insertion sequence element IS within a gene encoding an H-NS family transcriptional regulator. To confirm the role of H-NS in colistin resistance, we generated an deletion mutant in 6009-1and showed that colistin resistance increased upon the deletion of We also provided 6009-2 with an intact copy of and showed that the strain was no longer resistant to high concentrations of colistin. Transcriptomic analysis of the clinical isolates identified more than 150 genes as being differentially expressed in the colistin-resistant mutant 6009-2. Importantly, the expression of, encoding a second lipid A-specific pEtN transferase but not , was increased in the mutant. This is the first time an H-NS family transcriptional regulator has been associated with a pEtN transferase and colistin resistance.

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The contribution of PmrAB to the virulence of a clinical isolate ofEscherichia coli

Cited by 7 publications

References 24 publications

Mechanistic and biophysical characterization of polymyxin resistance response regulator PmrA in Acinetobacter baumannii

Mechanistic and biophysical characterization of polymyxin resistance response regulator PmrA in Acinetobacter baumannii

Acinetobacter baumannii under Acidic Conditions Induces Colistin Resistance through PmrAB Activation and Lipid A Modification

Emergence of High-Level Colistin Resistance in an Acinetobacter baumannii Clinical Isolate Mediated by Inactivation of the Global Regulator H-NS

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