{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T01:28:35Z","timestamp":1789954115502,"version":"4.0.1"},"reference-count":28,"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            Class C cephalosporinases are a growing threat, and inhibitors of these enzymes are currently unavailable. Studies exploring the YXN loop asparagine in the\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Escherichia coli<\/jats:named-content>\n            AmpC, P99, and CMY-2 enzymes have suggested that interactions between C6\u2032 or C7\u2032 substituents on penicillins or cephalosporins and this Asn are important in determining substrate specificity and enzymatic stability. We sought to characterize the YXN loop asparagine in the clinically important ADC-7 class C \u03b2-lactamase of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Acinetobacter baumannii<\/jats:named-content>\n            . Mutagenesis at the N148 position in ADC-7 yields functional mutants (N152G, -S, -T, -Q, -A, and -C) that retain cephalosporinase activity. Using standard assays, we show that N148G, -S, and -T variants possess good catalytic activity toward cefoxitin and ceftaroline but that cefepime is a poor substrate. Because N152 variants of CMY-2, another class C \u03b2-lactamase, are more readily inhibited by tazobactam due to higher rates of inactivation, we also tested if the N148 substitutions in ADC-7 would affect inactivation by sulfone inhibitors, sulbactam and tazobactam, class A \u03b2-lactamase, and\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. baumannii<\/jats:named-content>\n            penicillin-binding protein (PBP) inhibitors with\n            <jats:italic>in vitro<\/jats:italic>\n            activity against ADC-7. The 50% inhibitory concentrations (IC\n            <jats:sub>50<\/jats:sub>\n            s) for tazobactam and sulbactam were improved, with 7-fold and 2-fold reductions, respectively, for the N148S variant. A homology model of the N148S ADC-7 enzyme in a Michaelis-Menten complex with tazobactam showed a loss of interaction between N148 and the sulfone moiety of the inhibitor. We postulate that this may result in more-rapid secondary ring opening of the inhibitor, as the unbound sulfone is an excellent leaving group, leading to more-rapid formation of the stable linearized inhibitor.\n          <\/jats:p>","DOI":"10.1128\/aac.03537-14","type":"journal-article","created":{"date-parts":[[2014,12,23]],"date-time":"2014-12-23T03:11:33Z","timestamp":1419304293000},"page":"1472-1477","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Effect of Asparagine Substitutions in the YXN Loop of a Class C \u03b2-Lactamase of Acinetobacter baumannii on Substrate and Inhibitor Kinetics"],"prefix":"10.1128","volume":"59","author":[{"given":"Marion J.","family":"Skalweit","sequence":"first","affiliation":[{"name":"Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"},{"name":"Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"},{"name":"Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Li","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda A.","family":"Taracila","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.7.2941-2948.2005"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00036-08"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00050-10"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01261-13"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm070"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00704-11"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9015988"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja403598g"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01334-12"},{"key":"e_1_3_2_11_2","volume-title":"Abstr. 51st Intersci Conf Antimicrob Agents Chemother","author":"Skalweit MJ","year":"2011","unstructured":"Skalweit MJ, Li M, Conklin BC, Taracila M. 2011. C1-601 effect of N152G, -S and -T substitution on CMY-2 beta-lactamase activity and inhibition, poster C1-601. Abstr. 51st Intersci Conf Antimicrob Agents Chemother, Chicago, IL."},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03057-14"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02247-12"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.485979"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02625-14"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00023a023"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1110\/ps.073092407"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.40.6.1947-1957.2002"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_3_2_20_2","first-page":"63","article-title":"Development and validation of UV spectrophotometric method for quantitative estimation of ceftaroline fosamil in bulk and injection form","volume":"2","author":"Suneetha A","year":"2012","unstructured":"Suneetha A, China Venkanna K, Kathirvel S. 2012. Development and validation of UV spectrophotometric method for quantitative estimation of ceftaroline fosamil in bulk and injection form. Int J Pharm Res Anal 2:63\u201367.","journal-title":"Int J Pharm Res Anal"},{"key":"e_1_3_2_21_2","volume-title":"Evaluation of enzyme inhibitors in drug discovery","author":"Copeland RA","year":"2005","unstructured":"Copeland RA. 2005. Evaluation of enzyme inhibitors in drug discovery, 1st ed. 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