MgrB Mutations and Altered Cell Permeability in Colistin Resistance in Klebsiella pneumoniae

Yap, Polly Soo Xi; Cheng, Wan-Hee; Chang, Sook Keng; Lim, Swee-Hua Erin; Lai, Kok-Song

doi:10.3390/cells11192995

Cited by 15 publications

(12 citation statements)

References 60 publications

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“…For example, activation of a PhoPQ two-component system results in increased mgrB transcription, which then negatively suppresses the phosphorylation of PhoP. Mutations in mgrB prevent this negative feedback suppression of phosphorylation of PhoP, and, as a result, can alter colistin susceptibility [ 10 ]. Furthermore, efflux pump overexpression, porin loss and upregulation of capsular biosynthesis all have a role in colistin susceptibility [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Analysis of Innate Susceptibility Mechanisms of Escherichia coli to Colistin

et al. 2022

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Colistin is an antibiotic that has seen increasing clinical use for the treatment of human infections caused by Gram-negative pathogens, particularly due to the emergence of multidrug-resistant pathogens. Colistin resistance is also a growing problem and typically results from alterations to lipopolysaccharides mediated by phosphoethanolamine (pETn) transferase enzymes which can be encoded on the chromosome, or plasmids. In this study, we used ‘TraDIS-Xpress’ (Transposon Directed Insertion site Sequencing with expression), where a high-density transposon mutant library including outward facing promoters in Escherichia coli BW25113 identified genes involved in colistin susceptibility. We examined the genome-wide response of E. coli following exposure to a range of concentrations of colistin. Our TraDIS-Xpress screen confirmed the importance of overexpression of the two-component system basSR (which regulates pETn transferases) but also identified a wider range of genes important for survival in the presence of colistin, including genes encoding membrane associated proteins, DNA repair machinery, various transporters, RNA helicases, general stress response genes, fimbriae and phosphonate metabolism. Validation experiments supported a role in colistin susceptibility for novel candidate genes tested. TraDIS-Xpress is a powerful tool that expands our understanding of the wider landscape of genes involved in response to colistin susceptibility mechanisms.

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Section: Introductionmentioning

confidence: 99%

Genome-Wide Analysis of Innate Susceptibility Mechanisms of Escherichia coli to Colistin

et al. 2022

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“…The work of Timothy J and co-workers demonstrated that mgrB mutation induces PhoPQ-governed lipid A remodeling, which not only confers not only resistance to polymyxins but also enhances K. pneumoniae virulence by decreasing antimicrobial peptide susceptibility and attenuating early host defense response activation. 44,45 Resistance to colistin and polymyxin B is associated with lipid A remodeling. In this study, lipid A was also extracted from the RA-LZ01 and RA-LZ01ΔRaEptA using a method for isolation of lipid A F I G U R E 4 MALDI-TOF mass spectrometry determination of altered structures of LPS-lipid A anchored on the bacterial surface upon the expression of RaEptA and its 5-point mutants.…”

Section: Discussionmentioning

confidence: 99%

“…This may demonstrate a divergent scenario whereby an AMR mechanism helps to enhance virulence. The work of Timothy J and co‐workers demonstrated that mgrB mutation induces PhoPQ‐governed lipid A remodeling, which not only confers not only resistance to polymyxins but also enhances K. pneumoniae virulence by decreasing antimicrobial peptide susceptibility and attenuating early host defense response activation 44,45 . Resistance to colistin and polymyxin B is associated with lipid A remodeling.…”

Section: Discussionmentioning

confidence: 99%

EptA of Riemerella anatipestifer mediates phenotypes involved in colistin resistance and virulence

Chen

Quan

et al. 2023

The FASEB Journal

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Colistin (polymyxin E) is a group of cationic antimicrobial cyclic peptides and is recognized as a last‐resort defense against lethal infections with carbapenem‐resistant pathogens. In addition to the plasmid‐borne mobilized phosphoethanolamine (PEA) transferases, the functional expression of lipid A‐modifying enzymes encoded on chromosomes has been attributed to intrinsic bacterial colistin resistance. However, the mechanisms of colistin resistance in Riemerella anatipestifer remain unknown. Herein, the GE296_RS09715 gene‐encoded Lipid A PEA transferases (RaEptA) was identified in R. anatipestifer. Genetic and structural analyses revealed that the amino acid sequence of RaEptA shared 26.6%–33.1% similarities with the family of Lipid A PEA transferases (EptA) and MCR‐like proteins and have defined 12 residues that contribute to the formation of phosphatidylethanolamine (PE)‐recognizable cavities. Comparative analyses of colistin resistance in RA‐LZ01 and RA‐LZ01ΔRaEptA showed the level of colistin has fallen from 96 μg mL−1 down to 24 ~ 32 μg mL−1. Site‐directed mutagenesis assay of the PE‐binding cavity and expression of the mutants reveals that K309‐rRaEptA can remodel the surface of Escherichia coli and rendering it resistant to colistin, suggesting this point‐mutation of P309K is necessary for EptA‐mediated lipid A modification. Moreover, the virulence of RA‐LZ01ΔRaEptA was attenuated compared with RA‐LZ01 both in vivo and vitro. Taken together, the results represent the RaEptA involved in the colistin resistance and pathogenicity, and the P309K mutation might alter bacterial adaptation and increase the spread of colistin resistance from R. anatipestifer to other gram‐negative bacteria. The findings of this study suggest another scenario for the spread of colistin resistance genes and should be considered by a wide audience.

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“…The mgrB gene, a small transmembrane protein with 47 amino acids spanning the inner membrane, plays a role in negatively regulating PhoP phosphorylation-a process vital for bacterial outer membrane lipid biosynthesis. (29,30) Recent studies have demonstrated that nonmcr-associated CLR is frequently linked to alterations in the mgrB gene, as well as variations in the crrB, pmrB, phoQ, pmrA, and phoP genes. (29,30) Isolates carrying mcr genes exhibited resistance to colistin by the microdilution test (MIC ≤ 4 mg/L), and remarkably, all of these isolates displayed identical PFGE patterns, indicating their origin from a single clone.…”

Section: Discussionmentioning

confidence: 99%

“…(29,30) Recent studies have demonstrated that nonmcr-associated CLR is frequently linked to alterations in the mgrB gene, as well as variations in the crrB, pmrB, phoQ, pmrA, and phoP genes. (29,30) Isolates carrying mcr genes exhibited resistance to colistin by the microdilution test (MIC ≤ 4 mg/L), and remarkably, all of these isolates displayed identical PFGE patterns, indicating their origin from a single clone. Similar data were observed in Jordan, where out of 179 CRKP isolates, only one carried the mcr-1 gene, and the prevalence was 1.1%.…”

Section: Discussionmentioning

confidence: 99%

Genotypic characterization and detection of resistance mechanisms in carbapenem- resistant Klebsiella pneumoniae isolated from four tertiary care hospitals in Iran

Davoodi,

Soleimani,

Hosseini

et al. 2023

Preprint

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Background The global emergence of genes responsible for carbapenemases and the production of mcr in Klebsiella pneumoniae isolates pose a serious threat to public health. The study of carbapenem and colistin resistance (CLR) in K. pneumoniae has a high priority for the infection control committee. The purpose of this study was to determine the antimicrobial resistance rate and evaluate the pattern of CLR in carbapenem-resistant K. pneumoniae (CRKP) isolated from four tertiary care hospitals in Iran, as well as to describe the clonal relationship of multidrug-resistant K. pneumoniae strains. Fifty clinical isolates of CRKP were obtained from four hospitals in Iran. The mcr-harboring isolates and carbapenemase-encoding genes were screened by PCR amplification, and molecular typing (PFGE) was used to assess their spread. Among the total isolates, 38% were identified as CLR by colistin disk elution. Results Among positive isolates for carbapenemase genes, the most frequent gene was blaOXA−48. Additionally, the mcr-1 gene was detected in 6% of the obtained isolates; none of the other mcr genes were detected in the studied isolates. All isolates were grouped under four clusters (A-D). The major cluster was related to the C cluster with 23 isolates. Conclusions The prevalence of CLR K. pneumoniae was estimated to be 18% in our ICU. Colistin-resistant CRKP is becoming an emerging threat in ICU settings, limiting further treatment options. Additionally, we observed a common molecular signature among CRKP isolates. Therefore, hospitals need to implement an effective infection control system to prevent the outbreak of diverse carbapenem- and colistin-resistant isolates in the future.

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MgrB Mutations and Altered Cell Permeability in Colistin Resistance in Klebsiella pneumoniae

Cited by 15 publications

References 60 publications

Genome-Wide Analysis of Innate Susceptibility Mechanisms of Escherichia coli to Colistin

Genome-Wide Analysis of Innate Susceptibility Mechanisms of Escherichia coli to Colistin

EptA of Riemerella anatipestifer mediates phenotypes involved in colistin resistance and virulence

Genotypic characterization and detection of resistance mechanisms in carbapenem- resistant Klebsiella pneumoniae isolated from four tertiary care hospitals in Iran

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