Correlation of the expression of acrB and the regulatory genes marA, soxS and ramA with antimicrobial resistance in clinical isolates of Klebsiella pneumoniae endemic to New York City

Bratu, Simona; Landman, David; George, Avrille; Salvani, Jerome; Quale, John

doi:10.1093/jac/dkp186

Cited by 66 publications

(46 citation statements)

References 23 publications

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“…By examining more clinical isolates, we found no linear relationship between the acrB expression levels and tigecycline MICs. The overexpression of acrAB may have resulted from mutations in its local repressor acrR and changes in the expression of global transcriptional regulators of the AraC family, such as ramA and SoxS (28) . Our results demonstrated that there were no mutations in acrR of all tested isolates.…”

Section: Discussionmentioning

confidence: 99%

Over expression of AdeABC and AcrAB-TolC efflux systems confers tigecycline resistance in clinical isolates of Acinetobacter baumannii and Klebsiella pneumoniae

Yin

Ziyun

Zhang

et al. 2016

Rev. Soc. Bras. Med. Trop.

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Section: Discussionmentioning

confidence: 99%

Over expression of AdeABC and AcrAB-TolC efflux systems confers tigecycline resistance in clinical isolates of Acinetobacter baumannii and Klebsiella pneumoniae

Yin

Ziyun

Zhang

et al. 2016

Rev. Soc. Bras. Med. Trop.

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“…Alternatively, FarR may still function as repressor of farE in the absence of inducer, and then in the presence of exogenous fatty acid it may serve to promote expression of a positive-acting transcription factor that is needed to activate farE. This would partially conform to the AcrR-AcrB paradigm, where AcrR ensures that acrB is not expressed in the absence of an inducing stimulus, but other positive-acting factors are required to activate acrB (84)(85)(86). With these considerations in mind, work is in progress to determine the mechanism of FarR-dependent regulation of gene expression through analysis of its interaction with different fatty acids and target promoters and the scope of genes that are affected by this interaction.…”

Section: Discussionmentioning

confidence: 99%

Inducible Expression of a Resistance-Nodulation-Division-Type Efflux Pump in Staphylococcus aureus Provides Resistance to Linoleic and Arachidonic Acids

et al. 2015

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Although Staphylococcus aureus is exposed to antimicrobial fatty acids on the skin, in nasal secretions, and in abscesses, a specific mechanism of inducible resistance to this important facet of innate immunity has not been identified. Here, we have sequenced the genome of S. aureus USA300 variants selected for their ability to grow at an elevated concentration of linoleic acid. The fatty acid-resistant clone FAR7 had a single nucleotide polymorphism resulting in an H 121 Y substitution in an uncharacterized transcriptional regulator belonging to the AcrR family, which was divergently transcribed from a gene encoding a member of the resistance-nodulation-division superfamily of multidrug efflux pumps. We named these genes farR and farE, for regulator and effector of fatty acid resistance, respectively. Several lines of evidence indicated that FarE promotes efflux of antimicrobial fatty acids and is regulated by FarR. First, expression of farE was strongly induced by arachidonic and linoleic acids in an farRdependent manner. Second, an H 121 Y substitution in FarR resulted in increased expression of farE and was alone sufficient to promote increased resistance of S. aureus to linoleic acid. Third, inactivation of farE resulted in a significant reduction in the inducible resistance of S. aureus to the bactericidal activity of 100 M linoleic acid, increased accumulation of [ 14 C]linoleic acid by growing cells, and severely impaired growth in the presence of nonbactericidal concentrations of linoleic acid. Cumulatively, these findings represent the first description of a specific mechanism of inducible resistance to antimicrobial fatty acids in a Gram-positive pathogen. IMPORTANCEStaphylococcus aureus colonizes approximately 25% of humans and is a leading cause of human infectious morbidity and mortality. To persist on human hosts, S. aureus must have intrinsic defense mechanisms to cope with antimicrobial fatty acids, which comprise an important component of human innate defense mechanisms. We have identified a novel pair of genes, farR and farE, that constitute a dedicated regulator and effector of S. aureus resistance to linoleic and arachidonic acids, which are major fatty acids in human membrane phospholipid. Expression of farE, which encodes an efflux pump, is induced in an farRdependent mechanism, in response to these antimicrobial fatty acids that would be encountered in a tissue abscess. Staphylococcus aureus has a dichotomous relation with human hosts, being able to establish an asymptomatic commensal relationship, but is also historically known as a leading cause of human infectious morbidity and mortality. Significantly, death attributed to S. aureus in the United States is now comparable to mortality rates for AIDS, tuberculosis, and viral hepatitis (1-3). Not surprisingly, therefore, S. aureus has been the subject of intensive research on mechanisms of pathogenesis and acquisition and transfer of antibiotic resistance and of efforts to identify potential vaccine antigens (4-6). Until the late ...

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“…The transcription of the acrAB genes is controlled by several transcriptional activators of the AraC/XylS family, RamA, MarA, SoxS, and RobA, which interact with the acrAB promoter, increasing the production of AcrAB proteins and enhancing efflux (19,22,25). The transcriptional activators of the acrAB genes are themselves controlled by other trans-acting factors.…”

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confidence: 99%

Genomics of KPC-Producing Klebsiella pneumoniae Sequence Type 512 Clone Highlights the Role of RamR and Ribosomal S10 Protein Mutations in Conferring Tigecycline Resistance

Villa

Feudi

Fortini

et al. 2014

Antimicrob Agents Chemother

115

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Full genome sequences were determined for five Klebsiella pneumoniae strains belonging to the sequence type 512 (ST512) clone, producing KPC-3. Three strains were resistant to tigecycline, one showed an intermediate phenotype, and one was susceptible. Comparative analysis performed using the genome of the susceptible strain as a reference sequence identified genetic differences possibly associated with resistance to tigecycline. Results demonstrated that mutations in the ramR gene occurred in two of the three sequenced strains. Mutations in RamR were previously demonstrated to cause overexpression of the AcrABTolC efflux system and were implicated in tigecycline resistance in K. pneumoniae. The third strain showed a mutation located at the vertex of a very well conserved loop in the S10 ribosomal protein, which is located in close proximity to the tigecycline target site in the 30S ribosomal subunit. This mutation was previously shown to be associated with tetracycline resistance in Neisseria gonorrhoeae. A PCR-based approach was devised to amplify the potential resistance mechanisms identified by genomics and applied to two additional ST512 strains showing resistance to tigecycline, allowing us to identify mutations in the ramR gene.

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Correlation of the expression of acrB and the regulatory genes marA, soxS and ramA with antimicrobial resistance in clinical isolates of Klebsiella pneumoniae endemic to New York City

Cited by 66 publications

References 23 publications

Over expression of AdeABC and AcrAB-TolC efflux systems confers tigecycline resistance in clinical isolates of Acinetobacter baumannii and Klebsiella pneumoniae

Over expression of AdeABC and AcrAB-TolC efflux systems confers tigecycline resistance in clinical isolates of Acinetobacter baumannii and Klebsiella pneumoniae

Inducible Expression of a Resistance-Nodulation-Division-Type Efflux Pump in Staphylococcus aureus Provides Resistance to Linoleic and Arachidonic Acids

Genomics of KPC-Producing Klebsiella pneumoniae Sequence Type 512 Clone Highlights the Role of RamR and Ribosomal S10 Protein Mutations in Conferring Tigecycline Resistance

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