Effects of Regulatory Network Organization and Environment on PmrD Connector Activity and Polymyxin Resistance in
            <i>Klebsiella pneumoniae</i>
            and
            <i>Escherichia coli</i>

Chen, Annie I.; Albicoro, Francisco Javier; Zhu, Jun; Goulian, Mark

doi:10.1128/aac.00889-20

Cited by 14 publications

(12 citation statements)

References 62 publications

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“…Although PmrD in E. coli cannot function in the same manner as Salmonella , it is required for the modification of lipid A in E. coli under low Mg 2+ growth conditions ( Rubin et al, 2015 ). In Klebsiella pneumoniae , the arn operon can not only be regulated directly by PhoP/PhoQ, but also indirectly through PmrD ( Chen et al, 2021 ). In Yersinia pestis , despite the lack of PmrD, protein lipid A with L-Ara4N can be promoted by PhoP dependently and independently through different inducing signals ( Winfield et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

“…And PhoP is a phosphorylated response regulator which is controlled by activated PhoQ ( Simpson and Trent, 2019 ). PhoP directly regulates a set of genes that vary among different bacteria ( Winfield et al, 2005 ; Hong et al, 2018 ; Chen et al, 2021 ). However, some Gram-negative bacteria have conserved ancestral genes, such as mgtA in Escherichia coli acting as magnesium transporter and mgrB as the direct negative regulator of PhoP/PhoQ ( Minagawa et al, 2003 ; Zwir et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“… Schematic of PhoP/PhoQ and PmrA/PmrB regulation network in different genera of Enterobacteriaceae ( Winfield et al, 2005 ; Rubin et al, 2015 ; Hong et al, 2018 ; Chen et al, 2021 ). PmrD functions as a connector between PhoP/PhoQ and PmrA/PmrB in Salmonella enterica (A) .…”

Section: Introductionmentioning

confidence: 99%

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The Role of the Two-Component System PhoP/PhoQ in Intrinsic Resistance of Yersinia enterocolitica to Polymyxin

et al. 2022

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Polymyxin is the “last resort” of antibiotics. The self-induced resistance to polymyxin in Gram-negative bacteria could be mediated by lipopolysaccharide (LPS) modification, which is regulated by the two-component system, PhoP/PhoQ. Yersinia enterocolitica is a common foodborne pathogen. However, PhoP/PhoQ has not been thoroughly studied in Y. enterocolitica. In this study, the functions of PhoP/PhoQ in Y. enterocolitica intrinsic resistance were investigated. The resistance of Y. enterocolitica was found to decrease with the deletion of PhoP/PhoQ. Further, PhoP/PhoQ was found to play an important role in maintaining membrane permeability, intercellular metabolism, and reducing membrane depolarization. Based on subsequent studies, the binding ability of polymyxin to Y. enterocolitica was decreased by the modification of LPS with structures, such as L-Ara4N and palmitate. Analysis of the gene transcription levels revealed that the LPS modification genes, pagP and arn operon, were downregulated with the deletion of PhoP/PhoQ in Y. enterocolitica during exposure to polymyxin. In addition, pmrA, pmrB, and eptA were downregulated in the mutants compared with the wild-type strain. Such findings demonstrate that PhoP/PhoQ contributes to the intrinsic resistance of Y. enterocolitica toward polymyxins. LPS modification with L-Ara4N or palmitate is mainly responsible for the resistance of Y. enterocolitica to polymyxins. The transcription of genes related to LPS modification and PmrA/PmrB can be both affected by PhoP/PhoQ in Y. enterocolitica. This study adds to current knowledge regarding the role of PhoP/PhoQ in intrinsic resistance of Y. enterocolitica to polymyxin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Role of the Two-Component System PhoP/PhoQ in Intrinsic Resistance of Yersinia enterocolitica to Polymyxin

et al. 2022

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“…The TCS PhoPQ and PmrAB in K. pneumoniae and E. coli are controlled by additional proteins, MgrB, a negative regulator of PhoQ, and PmrD-a connector protein that activates PmrAB in response to PhoPQ stimulation ( Chen et al., 2021 ). In regulating the polymyxin resistance, PmrD is dependent on the network organization as well as PmrB stimulation.…”

Section: The Two-component Systemmentioning

confidence: 99%

Deciphering the genetic network and programmed regulation of antimicrobial resistance in bacterial pathogens

Ramamurthy

Ghosh

Chowdhury

et al. 2022

Front. Cell. Infect. Microbiol.

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Antimicrobial resistance (AMR) in bacteria is an important global health problem affecting humans, animals, and the environment. AMR is considered as one of the major components in the “global one health”. Misuse/overuse of antibiotics in any one of the segments can impact the integrity of the others. In the presence of antibiotic selective pressure, bacteria tend to develop several defense mechanisms, which include structural changes of the bacterial outer membrane, enzymatic processes, gene upregulation, mutations, adaptive resistance, and biofilm formation. Several components of mobile genetic elements (MGEs) play an important role in the dissemination of AMR. Each one of these components has a specific function that lasts long, irrespective of any antibiotic pressure. Integrative and conjugative elements (ICEs), insertion sequence elements (ISs), and transposons carry the antimicrobial resistance genes (ARGs) on different genetic backbones. Successful transfer of ARGs depends on the class of plasmids, regulons, ISs proximity, and type of recombination systems. Additionally, phage-bacterial networks play a major role in the transmission of ARGs, especially in bacteria from the environment and foods of animal origin. Several other functional attributes of bacteria also get successfully modified to acquire ARGs. These include efflux pumps, toxin-antitoxin systems, regulatory small RNAs, guanosine pentaphosphate signaling, quorum sensing, two-component system, and clustered regularly interspaced short palindromic repeats (CRISPR) systems. The metabolic and virulence state of bacteria is also associated with a range of genetic and phenotypic resistance mechanisms. In spite of the availability of a considerable information on AMR, the network associations between selection pressures and several of the components mentioned above are poorly understood. Understanding how a pathogen resists and regulates the ARGs in response to antimicrobials can help in controlling the development of resistance. Here, we provide an overview of the importance of genetic network and regulation of AMR in bacterial pathogens.

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“…Such modifications of lipid A could diminish the electrostatic affinity with polymyxin, reducing attachment of polymyxin to the external membrane of bacteria ( Aye et al, 2020 ). In Enterobacteriaceae , many genes regulated by the two-component system (TCS) PhoP/PhoQ and PmrA/PmrB can confer polymyxin resistance, and PhoP/PhoQ is able to activate PmrAB TCS through the connector PmrD ( Chen et al, 2021 ). In K. pneumoniae , addition of L-Ara4N is achieved by mutations in PhoP/PhoQ and PmrA/PmrB TCS and the following constitutive expression of the arnBCADTEF operon ( Sun et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Cell Membrane Remodeling Mediates Polymyxin B Resistance in Klebsiella pneumoniae: An Integrated Proteomics and Metabolomics Study

et al. 2022

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Polymyxin B (PB) is introduced into the clinic as the last-line therapy against carbapenem-resistant Klebsiella pneumoniae (CRKP). Unfortunately, increased resistance to PB in Klebsiella pneumoniae (K. pneumoniae) has threatened global health. Resistance of K. pneumoniae to PB was induced by passaging in serial concentrations of PB and determined by microbroth dilution method. Growth characteristics of induced strains including growth curve, reversibility of resistance, and biofilm formation (crystal violet staining method) were measured. This study employed TMT-labeled quantitative proteomics and LC-MS/MS metabolomics analysis to investigate the key biological processes associated with PB resistance in K. pneumoniae. A total of 315 differentially expressed proteins (DEPs) were identified, of which 133 were upregulated and 182 were downregulated in the PB-resistant K. pneumoniae. KEGG enrichment analysis revealed that the DEPs were mainly involved in ATP-binding cassette (ABC) transporters and cationic antimicrobial peptide (CAMP) resistance. Proteins related to central carbon metabolism were inhibited in the PB-resistant K. pneumoniae, but proteins mediating LPS modification were activated. Transcriptional levels of CAMP resistance-related proteins were significantly different between PB-susceptible and -resistant K. pneumoniae. PB treatment led to an increase in reactive oxygen species (ROS) levels of K. pneumoniae. Metabolomics data demonstrated that 23 metabolites were significantly upregulated in PB-resistant K. pneumoniae and 5 were downregulated. The differential metabolites were mainly lipids, including glycerophospholipids, sphingolipids, and fatty acids. Exposure to PB resulted in increased level of phospholipid transport gene mlaF in K. pneumoniae. Our study suggested that membrane remodeling and inhibited central carbon metabolism are conducive to the development of PB resistance in K. pneumoniae.

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Effects of Regulatory Network Organization and Environment on PmrD Connector Activity and Polymyxin Resistance in Klebsiella pneumoniae and Escherichia coli

Cited by 14 publications

References 62 publications

The Role of the Two-Component System PhoP/PhoQ in Intrinsic Resistance of Yersinia enterocolitica to Polymyxin

The Role of the Two-Component System PhoP/PhoQ in Intrinsic Resistance of Yersinia enterocolitica to Polymyxin

Deciphering the genetic network and programmed regulation of antimicrobial resistance in bacterial pathogens

Cell Membrane Remodeling Mediates Polymyxin B Resistance in Klebsiella pneumoniae: An Integrated Proteomics and Metabolomics Study

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