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• W4308200511 abstract "Aztreonam-avibactam is a promising combination to treat carbapenem-resistant Enterobacterales including coverage for metallo-β-lactamases. Escherichia coli strains resistant to aztreonam-avibactam have emerged but resistance mechanisms remain to be elucidated. We performed a study to investigate the mechanism for aztreonam-avibactam in a carbapenem-resistant Escherichia coli clinical strain. This strain was resistant to aztreonam-avibactam (aztreonam MIC, 16 mg/L in the presence of 4 mg/L avibactam). Whole genome sequencing revealed that the strain carried metallo-β-lactamase gene bla NDM-4 and the extended-spectrum β-lactamase (ESBL) gene bla CTX-M-15 and had a YRIK four amino acid insertion in penicillin-binding protein 3 (PBP3). bla CTX-M-15 was cloned into pET-28a(+), followed by the transformation, with the gene, of E. coli strain 035125∆pCMY42 possessing the YRIK insertion in PBP3 and strain BL21 with the wildtype PBP3. bla CTX-M-14 , another common ESBL gene, and bla CTX-M-199 , a hybrid of bla CTX-M-14 and bla CTX-M-15 were also individually cloned into both E. coli strains for comparison. Aztreonam-avibactam resistance was only observed in the E. coli strains with the YRIK insertion in PBP3 that produced CTX-M-15 or its hybrid enzyme CTX-M-199. Checkerboard titration assays were performed to determine the synergistic effects between aztreonam-avibactam and ceftazidime or meropenem. Doubling avibactam concentration in vitro reversed aztreonam-avibactam resistance, while the combination of aztreonam-avibactam and ceftazidime or meropenem did not. In conclusion, CTX-M enzymes with activity against aztreonam, (e.g., CTX-M-15 and CTX-M-199), can confer resistance in the combination of PBP3 with YRIK insertions in metallo-β-lactamase-producing carbapenem-resistant E. coli . Doubling the concentration of avibactam may overcome such resistance." @default.
• W4308200511 created "2022-11-09" @default.
• W4308200511 creator A5023200478 @default.
• W4308200511 creator A5059888240 @default.
• W4308200511 date "2022-11-04" @default.
• W4308200511 modified "2023-10-15" @default.
• W4308200511 title "Resistance to aztreonam-avibactam due to CTX-M-15 in the presence of penicillin-binding protein 3 with extra amino acids in Escherichia coli" @default.
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• W4308200511 doi "https://doi.org/10.3389/fmicb.2022.1047109" @default.
• W4308200511 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36406430" @default.
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