{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:27:32Z","timestamp":1789172852202,"version":"build-2803163510"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2015,3,1]],"date-time":"2015-03-01T00:00:00Z","timestamp":1425168000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Resistance to \u03b2-lactams is constantly increasing due to the emergence of totally new enzymes but also to the evolution of preexisting \u03b2-lactamases. GES-1 is a clinically relevant extended-spectrum \u03b2-lactamase (ESBL) that hydrolyzes penicillins and broad-spectrum cephalosporins but spares monobactams and carbapenems. However, several GES-1 variants (i.e., GES-2 and GES-5) previously identified among clinical isolates display an extended spectrum of activity toward carbapenems. To study the evolution potential of the GES-1 \u03b2-lactamase, this enzyme was submitted to\n                    <jats:italic>in vitro<\/jats:italic>\n                    -directed evolution, with selection on increasing concentrations of the cephalosporin cefotaxime, the monobactam aztreonam, or the carbapenem imipenem. The highest resistance levels were conferred by a combination of up to four substitutions. The A6T-E104K-G243A variant selected on cefotaxime and the A6T-E104K-T237A-G243A variant selected on aztreonam conferred high resistance to cefotaxime, ceftazidime, and aztreonam. Conversely, the A6T-G170S variant selected on imipenem conferred high resistance to imipenem and cefoxitin. Of note, the A6T substitution involved in higher MICs for all \u03b2-lactams is located in the leader peptide of the GES enzyme and therefore is not present in the mature protein. Acquired cross-resistance was not observed, since selection with cefotaxime or aztreonam did not select for resistance to imipenem, and vice versa. Here, we demonstrate that the \u03b2-lactamase GES-1 exhibits peculiar properties, with a significant potential to gain activity against broad-spectrum cephalosporins, monobactams, and carbapenems.\n                  <\/jats:p>","DOI":"10.1128\/aac.04450-14","type":"journal-article","created":{"date-parts":[[2015,1,5]],"date-time":"2015-01-05T22:55:44Z","timestamp":1420498544000},"page":"1664-1670","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":31,"title":["<i>In Vitro<\/i>\n                    Prediction of the Evolution of GES-1 \u03b2-Lactamase Hydrolytic Activity"],"prefix":"10.1128","volume":"59","author":[{"given":"S\u00e9verine","family":"Bontron","sequence":"first","affiliation":[{"name":"Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Poirel","sequence":"additional","affiliation":[{"name":"Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland"},{"name":"INSERM U914 Emerging Resistance to Antibiotics, Facult\u00e9 de M\u00e9decine et Universit\u00e9 Paris Sud, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Nordmann","sequence":"additional","affiliation":[{"name":"Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland"},{"name":"INSERM U914 Emerging Resistance to Antibiotics, Facult\u00e9 de M\u00e9decine et Universit\u00e9 Paris Sud, Le Kremlin-Bic\u00eatre, France"},{"name":"HFR-H\u00f4pital Cantonal de Fribourg, Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2760269"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10156-013-0640-7"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2010.09.006"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161213804070320"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2007.01861.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.3.622-632.2000"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2012.02.008"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.8.3593-3597.2005"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.9.2598-2603.2001"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00773-10"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.06841-11"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/1574-6968.12340"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02271-13"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444907036955"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00453-09"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2007.02.013"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2012.03.010"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2805"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzg057"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1994.tb00469.x"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.02407-12"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.011262"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja308197j"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2007.01854.x"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2007.01863.x"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2010.00222.x"},{"key":"e_1_3_3_28_2","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1042\/bj2560669","article-title":"Evidence for an oxyanion hole in serine \u03b2-lactamases and dd-peptidases","volume":"256","author":"Murphy BP","year":"1988","unstructured":"Murphy BP, Pratt RF. 1988. 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