Genetic characterization of tigecycline resistance in clinical isolates of Enterobacter cloacae and Enterobacter aerogenes

Veleba, Mark; Majumdar, Shyamasree De; Hornsey, Michael; Woodford, Neil; Schneiders, Thamarai

doi:10.1093/jac/dks530

Cited by 52 publications

(38 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, it appeared that, in addition to the AcrAB pump, ECL_01758 and ECL_00054 had tigecycline as the substrate (Table 4). This is of clinical importance for the control of the emergence of tigecycline-resistant strains, since this molecule is increasingly used to fight against MDR Enterobacter (42)(43)(44) Lastly, the plasmid carrying ECL_02124-02125 (annotated as oqxAB genes and transcriptionally induced 743-fold) restored the wild-type phenotype, except for tetracycline, tigecycline, erythromycin, and acridine orange (Tables 3 and 4). The MICs of the fluoroquinolones tested (except moxifloxacin) were even 4-fold higher than those of the wild-type strain (Tables 3 and 4).…”

Section: Resultsmentioning

confidence: 99%

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

Guérin

Lallement

Isnard

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

cIn Gram-negative bacteria, the active efflux is an important mechanism of antimicrobial resistance, but little is known about the Enterobacter cloacae complex (ECC). It is mediated primarily by pumps belonging to the RND (resistance-nodulation-cell division) family, and only AcrB, part of the AcrAB-TolC tripartite system, was characterized in ECC. However, detailed genome sequence analysis of the strain E. cloacae subsp. cloacae ATCC 13047 revealed to us that 10 other genes putatively coded for RNDtype transporters. We then characterized the role of all of these candidates by construction of corresponding deletion mutants, which were tested for their antimicrobial susceptibility to 36 compounds, their virulence in the invertebrate Galleria mellonella model of infection, and their ability to form biofilm. Only the ⌬acrB mutant displayed significantly different phenotypes compared to that of the wild-type strain: 4-to 32-fold decrease of MICs of several antibiotics, antiseptics, and dyes, increased production of biofilm, and attenuated virulence in G. mellonella. In order to identify specific substrates of each pump, we individually expressed in trans all operons containing an RND pump-encoding gene into the ⌬acrB hypersusceptible strain. We showed that three other RND-type efflux systems (ECL_00053-00055, ECL_01758-01759, and ECL_02124-02125) were able to partially restore the wild-type phenotype and to superadd to and even enlarge the broad range of antimicrobial resistance. This is the first global study assessing the role of all RND efflux pumps chromosomally encoded by the ECC, which confirms the major role of AcrB in both pathogenicity and resistance and the potential involvement of other RND-type members in acquired resistance.

show abstract

Section: Resultsmentioning

confidence: 99%

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

Guérin

Lallement

Isnard

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Enterobacter spp. develop resistance to tigecycline through AcrAB overproduction (during ciprofloxacin treatment in one study [267]), and this was caused by the overproduction of the RamA regulator (268), although one study concluded that the overexpression of RamA, an not necessarily that of AcrAB, correlated with the resistance, suggesting the involvement of other efflux pumps (269).…”

Section: Enterobacter Aerogenes and Enterobacter Cloacaementioning

confidence: 99%

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

2015

View full text Add to dashboard Cite

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.

show abstract

“…Previous studies have examined TGC resistance mechanism in Enterobacteriaceae (17,18). Reductions in the TGC susceptibility of E. coli laboratory strains and clinical isolates are accompanied by overexpression of AcrAB-TolC; however, these E. coli strains have never exceeded the breakpoint for TGC (Ͼ2 mg/liter) (19,20,27).…”

mentioning

confidence: 99%

Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H 30 R and O1-ST648

Sato

Suzuki

Shiraishi

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Tigecycline (TGC) is a last-line drug for multidrug-resistant Enterobacteriaceae. We investigated the mechanism(s) underlying TGC nonsusceptibility (TGC resistant/intermediate) in Escherichia coli clinical isolates. The MIC of TGC was determined for 277 fluoroquinolone-susceptible isolates (ciprofloxacin [CIP] MIC, Ͻ0.125 mg/liter) and 194 fluoroquinolone-resistant isolates (CIP MIC, Ͼ2 mg/liter). The MIC 50 and MIC 90 for TGC in fluoroquinolone-resistant isolates were 2-fold higher than those in fluoroquinolone-susceptible isolates (MIC 50 , 0.5 mg/liter versus 0.25 mg/liter; MIC 90 , 1 mg/liter versus 0.5 mg/liter, respectively). Two fluoroquinolone-resistant isolates (O25b:H4-ST131-H30R and O125:H37-ST48) were TGC resistant (MICs of 4 and 16 mg/liter, respectively), and four other isolates of O25b:H4-ST131-H30R and an isolate of O1-ST648 showed an intermediate interpretation (MIC, 2 mg/liter). No TGC-resistant/intermediate strains were found among the fluoroquinolone-susceptible isolates. The TGC-resistant/intermediate isolates expressed higher levels of acrA and acrB and had lower intracellular TGC concentrations than susceptible isolates, and they possessed mutations in acrR and/or marR. The MICs of acrAB-deficient mutants were markedly lower (0.25 mg/liter) than those of the parental strain. After continuous stepwise exposure to CIP in vitro, six of eight TGC-susceptible isolates had reduced TGC susceptibility. Two of them acquired TGC resistance (TGC MIC, 4 mg/liter) and exhibited expression of acrA and acrB and mutations in acrR and/or marR. In conclusion, a population of fluoroquinolone-resistant E. coli isolates, including major extraintestinal pathogenic lineages O25b:H4-ST131-H30R and O1-ST648, showed reduced susceptibility to TGC due to overexpression of the efflux pump AcrAB-TolC, leading to decreased intracellular concentrations of the antibiotics that may be associated with the development of fluoroquinolone resistance.

show abstract

Genetic characterization of tigecycline resistance in clinical isolates of Enterobacter cloacae and Enterobacter aerogenes

Cited by 52 publications

References 25 publications

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

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

Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H 30 R and O1-ST648

Contact Info

Product

Resources

About