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Antibiotic Trapping by Plasmid-Encoded CMY-2 β-Lactamase Combined with Reduced Outer Membrane Permeability as a Mechanism of Carbapenem Resistance in Escherichia coli
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| Zeitschriftentitel: | Antimicrobial Agents and Chemotherapy |
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| Personen und Körperschaften: | , , , , , , |
| In: | Antimicrobial Agents and Chemotherapy, 57, 2013, 8, S. 3941-3949 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>ABSTRACT</jats:title> <jats:p> A liver transplant patient was admitted with cholangitis, for which meropenem therapy was started. Initial cultures showed a carbapenem-susceptible (CS) <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Escherichia coli</jats:named-content> strain, but during admission, a carbapenem-resistant (CR) <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. coli</jats:named-content> strain was isolated. Analysis of the outer membrane protein profiles showed that both CS and CR <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. coli</jats:named-content> lacked the porins OmpF and OmpC. Furthermore, PCR and sequence analysis revealed that both CS and CR <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. coli</jats:named-content> possessed <jats:italic>bla</jats:italic> <jats:sub>CTX-M-15</jats:sub> and <jats:italic>bla</jats:italic> <jats:sub>OXA-1</jats:sub> . The CR <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. coli</jats:named-content> strain additionally harbored <jats:italic>bla</jats:italic> <jats:sub>CMY-2</jats:sub> and demonstrated a >15-fold increase in β-lactamase activity against nitrocefin, but no hydrolysis of meropenem was detected. However, nitrocefin hydrolysis appeared strongly inhibited by meropenem. Furthermore, the CMY-2 enzyme demonstrated lower electrophoretic mobility after its incubation either <jats:italic>in vitro</jats:italic> or <jats:italic>in vivo</jats:italic> with meropenem, indicative of its covalent modification with meropenem. The presence of the acyl-enzyme complex was confirmed by mass spectrometry. By transformation of the CMY-2-encoding plasmid into various <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. coli</jats:named-content> strains, it was established that both porin deficiency and high-level expression of the enzyme were needed to confer meropenem resistance. In conclusion, carbapenem resistance emerged by a combination of elevated β-lactamase production and lack of porin expression. Due to the reduced outer membrane permeability, only small amounts of meropenem can enter the periplasm, where they are trapped but not degraded by the large amount of the β-lactamase. This study, therefore, provides evidence that the mechanism of “trapping” by CMY-2 β-lactamase plays a role in carbapenem resistance. </jats:p> |
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| Umfang: | 3941-3949 |
| ISSN: |
0066-4804
1098-6596 |
| DOI: | 10.1128/aac.02459-12 |