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, Laura; Feudi, Claudia; Fortini, Daniela; García-Fernández, Aurora; Carattoli, Alessandra

doi:10.1128/aac.01803-13

Cited by 115 publications

(96 citation statements)

References 43 publications

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“…Therefore, as expected, no corresponding mutant could be obtained. In K. pneumoniae, it seems that the inactivation of the ramR gene (coding for an indirect negative regulator of the acrAB operon) is the most common mechanism conferring resistance to TIG (28). Nevertheless, it has recently been demonstrated that the resistance to TIG of the KPCproducing K. pneumoniae KP4-R strain was due to a Val57Leu substitution in the RpsJ protein sequence (28).…”

Section: Discussionmentioning

confidence: 99%

“…In K. pneumoniae, it seems that the inactivation of the ramR gene (coding for an indirect negative regulator of the acrAB operon) is the most common mechanism conferring resistance to TIG (28). Nevertheless, it has recently been demonstrated that the resistance to TIG of the KPCproducing K. pneumoniae KP4-R strain was due to a Val57Leu substitution in the RpsJ protein sequence (28). Moreover, as for the strains used in this study, the efflux did not appear to be involved in TIG resistance, pointing out that structural alteration of the ribosomal protein S10 in the drug target site may be a potential novel mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Genomic Analysis of Reduced Susceptibility to Tigecycline in Enterococcus faecium

Cattoir

Isnard

Cosquer

et al. 2015

Antimicrob Agents Chemother

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c Tigecycline (TIG) is approved for use for the treatment of complicated intra-abdominal infections, skin and skin structure infections, as well as pneumonia. Acquired resistance or reduced susceptibility to TIG has been observed in Gram-negative rods, has seldom been reported in Gram-positive organisms, and has not yet been reported in Enterococcus faecium. Using the serial passage method, in vitro mutant AusTig and in vitro mutants HMtig1 and HMtig2 with decreased TIG susceptibility (MICs, 0.25 g/ml) were obtained from strains E. faecium Aus0004 and HM1070 (MICs, 0.03 g/ml), respectively. In addition, two vancomycin-resistant E. faecium clinical isolates (EF16 and EF22) with reduced susceptibility to TIG (MICs, 0.5 and 0.25 g/ml, respectively) were studied. Compared to the wild-type strains, the in vitro mutants also showed an increase in the MICs of other tetracyclines. An efflux mechanism did not seem to be involved in the reduced TIG susceptibility, since the presence of efflux pump inhibitors (reserpine or pantoprazole) did not affect the MICs of TIG. Whole-genome sequencing of AusTig was carried out, and genomic comparison with the Aus0004 genome was performed. Four modifications leading to an amino acid substitution were found. These mutations affected the rpsJ gene (efau004_00094, coding for the S10 protein of the 30S ribosomal subunit), efau004_01228 (encoding a cation transporter), efau004_01636 (coding for a hypothetical protein), and efau004_02455 (encoding the L-lactate oxidase). The four other strains exhibiting reduced TIG susceptibility were screened for the candidate mutations. This analysis revealed that three of them showed an amino acid substitution in the same region of the RpsJ protein.In this study, we characterized for the first time genetic determinants linked to reduced TIG susceptibility in enterococci.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genomic Analysis of Reduced Susceptibility to Tigecycline in Enterococcus faecium

Cattoir

Isnard

Cosquer

et al. 2015

Antimicrob Agents Chemother

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“…ramR is located upstream of the romA and ramA genes and is transcribed divergently (787), and RamR binds to two sites of the romA-ram locus (788). Mutations in ramR can yield hyperproduction of RamA and AcrAB-TolC (300,787,788). Another AraC regulator, RarA, which is encoded by a gene upstream of the chromosomal oqxAB pump genes (chromosomal oqxAB genes are found only in K. pneumoniae to date), also positively controls the expression of AcrAB and OqxAB.…”

Section: K Pneumoniae Efflux Pumpsmentioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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“…Isolates were considered related if there was a 0-or 1-band difference. Finally, select isolates of K. pneumoniae were also examined for mutations in genes encoding RamR and ribosomal S10 proteins, using previously described primers and PCR conditions (11).…”

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confidence: 99%

Activity of Eravacycline against Enterobacteriaceae and Acinetobacter baumannii, Including Multidrug-Resistant Isolates, from New York City

Abdallah

Olafisoye

Cortes

et al. 2015

Antimicrob Agents Chemother

115

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Eravacycline demonstrated in vitro activity against a contemporary collection of more than 4,000 Gram-negative pathogens from New York City hospitals, with MIC 50 /MIC 90 values, respectively, for Escherichia coli of 0.12/0.5 g/ml, Klebsiella pneumoniae of 0.25/1 g/ml, Enterobacter aerogenes of 0.25/1 g/ml, Enterobacter cloacae 0.5/1 g/ml, and Acinetobacter baumannii of 0.5/1 g/ml. Activity was retained against multidrug-resistant isolates, including those expressing KPC and OXA carbapenemases. For A. baumannii, eravacycline MICs correlated with increased expression of the adeB gene.

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

Cited by 115 publications

References 43 publications

Genomic Analysis of Reduced Susceptibility to Tigecycline in Enterococcus faecium

Genomic Analysis of Reduced Susceptibility to Tigecycline in Enterococcus faecium

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Activity of Eravacycline against Enterobacteriaceae and Acinetobacter baumannii, Including Multidrug-Resistant Isolates, from New York City

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