{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T19:52:41Z","timestamp":1793303561140,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172309"],"award-info":[{"award-number":["82172309"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81861138055"],"award-info":[{"award-number":["81861138055"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    Aztreonam-avibactam is a promising combination to treat carbapenem-resistant Enterobacterales including coverage for metallo-\u03b2-lactamases.\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    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\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    clinical strain. This strain was resistant to aztreonam-avibactam (aztreonam MIC, 16\u2009mg\/L in the presence of 4\u2009mg\/L avibactam). Whole genome sequencing revealed that the strain carried metallo-\u03b2-lactamase gene\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>NDM-4<\/jats:sub>\n                    and the extended-spectrum \u03b2-lactamase (ESBL) gene\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>CTX-M-15<\/jats:sub>\n                    and had a YRIK four amino acid insertion in penicillin-binding protein 3 (PBP3).\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>CTX-M-15<\/jats:sub>\n                    was cloned into pET-28a(+), followed by the transformation, with the gene, of\n                    <jats:italic>E. coli<\/jats:italic>\n                    strain 035125\u2206pCMY42 possessing the YRIK insertion in PBP3 and strain BL21 with the wildtype PBP3.\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>CTX-M-14<\/jats:sub>\n                    , another common ESBL gene, and\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>CTX-M-199<\/jats:sub>\n                    , a hybrid of\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>CTX-M-14<\/jats:sub>\n                    and\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>CTX-M-15<\/jats:sub>\n                    were also individually cloned into both\n                    <jats:italic>E. coli<\/jats:italic>\n                    strains for comparison. Aztreonam-avibactam resistance was only observed in the\n                    <jats:italic>E. coli<\/jats:italic>\n                    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\n                    <jats:italic>in vitro<\/jats:italic>\n                    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-\u03b2-lactamase-producing carbapenem-resistant\n                    <jats:italic>E. coli<\/jats:italic>\n                    . Doubling the concentration of avibactam may overcome such resistance.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2022.1047109","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T05:03:42Z","timestamp":1667538222000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"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"],"prefix":"10.3389","volume":"13","author":[{"given":"Ke","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Zong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1093\/jac\/dku568","article-title":"Characterization of Escherichia coli NDM isolates with decreased susceptibility to aztreonam\/avibactam: role of a novel insertion in PBP3","volume":"70","author":"Alm","year":"2015","journal-title":"J. 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