Cloning and Functional Analysis of the Gene Encoding the 33- to 36-Kilodalton Outer Membrane Protein Associated with Carbapenem Resistance in
            <i>Acinetobacter baumannii</i>

Tomás, María; Beceiro, Alejandro; Pérez, Astrid; Velasco, David; Moure, Raquel; Villanueva, Rosa; Martı́nez-Beltrán, J; Bou, Germán

doi:10.1128/aac.49.12.5172-5175.2005

Cited by 99 publications

(48 citation statements)

References 22 publications

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“…In addition, there were no differences in the outer membrane protein profiles. These results were supported by the fact that the mRNA levels of the already known imipenem resistance-associated porins or outer membrane proteins, such as CarO, 33-to 36-kDa protein, and 43-kDa protein (3,6,11,20,24,33,35), did not show any significant differences between ISAB ab8 and ISAB ab8 (r) or ISAB ab1254 and ISAB ab1254(r) by RT-PCR. However, we could not exclude the hypothesis that decreased drug permeability was associated with imipenem resistance, and this resistance mechanism is found quite often as a drug resistance mechanism in bacteria.…”

Section: Discussionsupporting

confidence: 65%

“…Similar to most of the other OXA-type carbapenemases, the OXA-51-like enzymes show weak carbapenemase activity; however, the presence of the insertion sequence ISAba1 upstream of the bla OXA-51-like gene may provide a promoter that allows the overproduction of carbapenemase, and this results in carbapenem resistance (36). A few reports have demonstrated that a loss or decreased expression of an outer membrane protein or porin may be involved in resistance to carbapenems (3,6,11,20,24,33,35). However, there is less research supporting the association of increased expression of an outer membrane protein, which may form a component of an efflux pump, with carbapenem resistance (17,21,34).…”

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confidence: 99%

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An OXA-66/OXA-51-Like Carbapenemase and Possibly an Efflux Pump Are Associated with Resistance to Imipenem in Acinetobacter baumannii

Hu¹,

Yao²,

Fung³

et al. 2007

Antimicrob Agents Chemother

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We investigated the mechanisms involved in imipenem resistance in 23 clinical strains of Acinetobacter baumannii. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed the presence of a 30-kDa protein in imipenem-intermediate A. baumannii (IIAB) and imipenem-resistant A. baumannii (IRAB) strains; this protein was almost undetectable in imipenem-susceptible A. baumannii (ISAB) strains. The 30-kDa protein was identified as an OXA-51-like carbapenemase using two-dimensional gel electrophoresis and mass spectrometry. Similar to other recent findings, bla OXA-51-like genes were found to exist in all 23 clinical strains; however, the transcript levels of bla OXA-51-like in the IIAB and IRAB were higher than in the ISAB strains using reverse transcriptase PCR (RT-PCR) and real-time RT-PCR assays. This change was due to the presence of an insertion sequence, ISAba1, upstream of bla OXA-51-like in the IIAB and IRAB strains that was not present in the ISAB strains. The introduction of bla OXA-66 (a bla OXA-51-like gene), identified in ISAB ab1254 and IRAB ab1266, into Escherichia coli TOP10 cells resulted in 3.95-fold and 7.90-fold elevations in resistance to imipenem, respectively. Furthermore, when ISAB ab8 and ISAB ab1254 and their in vitro-selected imipenem-resistant mutants ISAB ab8(r) and ISAB ab1254(r) were compared, the results showed no change in the bla OXA-66 /bla OXA-51-like gene sequences, in expression of the gene, and in the outer membrane protein profiles. However, there was a four-to eightfold reduction in imipenem resistance upon adding carbonyl cyanide m-chlorophenylhydrazone. Taken together, these results suggest that the OXA-66/OXA-51-like carbapenemase contributes to intrinsic resistance to imipenem; however, drug export by an efflux pump may be more important and/or occur more frequently in imipenem-resistant A. baumannii. Furthermore, this is the first report of a Taiwanese strain of an OXA-66/OXA-51-like carbapenemase that confers imipenem resistance in A. baumannii.Acinetobacter baumannii accounts for a large percentage of nosocomial infections including pneumonia, bacteremia, skin infections, wound infections, and urinary tract infections (2, 19). Increasingly, multidrug resistance strains of A. baumannii have become common in hospitals worldwide and especially in intensive care units (10, 12, 30) and burn units (2,31,32,40). The types of resistance include many commonly used antibiotics such as aminoglycosides, fluoroquinolones, and ␤-lactams, although carbapenems are the most used antimicrobial drugs. However, an increasing number of recent studies reported the emergence of clinical A. baumannii strains that are resistance to imipenem (7,9,27).The mechanism of resistance to carbapenems in A. baumannii has mostly been ascribed to the acquisition of carbapenemases (1, 26) or to synergistic effects between ␤-lactamases with an ability to hydrolyze carbapenems and decreased expression of certain penicillin-binding proteins (13,14). The carbapenemases in A. baumannii ...

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

An OXA-66/OXA-51-Like Carbapenemase and Possibly an Efflux Pump Are Associated with Resistance to Imipenem in Acinetobacter baumannii

Hu¹,

Yao²,

Fung³

et al. 2007

Antimicrob Agents Chemother

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“…The role of Omps in antibiotic influx was partially characterized in carbapenem-resistant A. baumannii strains (Tomás et al, 2005). Expression of Omps, including CarO and 33 to 36 kDa Omp, was significantly decreased with increased resistance to carbapenems in A. baumannii strains.…”

Section: ~2mentioning

confidence: 99%

“…More specifically, cell wall and membrane proteomic analyses have become hot issues, because the alteration of membrane permeability is important for antimicrobial resistance (Siroy et al, 2006). However, very few outer membrane proteins (Omps) of A. baumannii strains have been identified and characterized as porins for the influx of drugs (Magnet et al, 2001;Limansky et al, 2002;Dupont et al, 2005;Mussi et al, 2005;Tomás et al, 2005).…”

mentioning

confidence: 99%

Proteomic analysis of outer membrane proteins from Acinetobacter baumannii DU202 in tetracycline stress condition

et al. 2008

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Acinetobacter baumannii readily developed antimicrobial resistance to clinically available antibiotics. A. baumannii DU202 is a multi-drug resistant strain, and is highly resistant to tetracycline (MIC>1,024 micro/ml). The surface proteome of A. baumannii DU202 in response to the sub-minimal inhibitory concentration (subMIC) of tetracycline was analyzed by 2-DE/MS-MS and 1-DE/LC/MS-MS to understand the pathways that form barriers for tetracycline. Membrane expression of major outer membrane proteins (Omps) was significantly decreased in response to the subMIC of tetracycline. These Omps with sizes of 38, 32, 28, and 21 kDa were identified as OmpA38, OmpA32, CarO, and OmpW, respectively. However, transcription level of these Omps was not significantly changed. 1-DE/LC/MS-MS analysis of secreted proteins showed that OmpA38, CarO, OmpW, and other Omps were increasingly secreted at tetracycline condition. This result suggests that A. baumannii actively regulates the membrane expression and the secretion of Omps to overcome antibiotic stress condition.

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“…Its elevated expression occurs in response to NaCl induction (523). Tetracycline-specific pumps such as Tet(A), Tet(B), and Tet39 were also found (16) and were frequently encoded both in chromosomal genomic resistance islands and by plasmids (496,500,562). Plasmid-borne tet(B)-tetR genes were associated with the ISCR2 mobile element in multidrug-resistant isolates (562), suggesting possible rapid horizontal resistance spread.…”

Section: Acinetobacter Sppmentioning

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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Cloning and Functional Analysis of the Gene Encoding the 33- to 36-Kilodalton Outer Membrane Protein Associated with Carbapenem Resistance in Acinetobacter baumannii

Cited by 99 publications

References 22 publications

An OXA-66/OXA-51-Like Carbapenemase and Possibly an Efflux Pump Are Associated with Resistance to Imipenem in Acinetobacter baumannii

An OXA-66/OXA-51-Like Carbapenemase and Possibly an Efflux Pump Are Associated with Resistance to Imipenem in Acinetobacter baumannii

Proteomic analysis of outer membrane proteins from Acinetobacter baumannii DU202 in tetracycline stress condition

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

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