{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:05:21Z","timestamp":1791273921381,"version":"4.1.0"},"reference-count":34,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"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":[[2015,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            \u03b2-Lactamase enzymes (EC 3.5.2.6) are a significant threat to the continued use of \u03b2-lactam antibiotics to treat infections. A novel non-\u03b2-lactam \u03b2-lactamase inhibitor with activity against many class A and C and some class D \u03b2-lactamase variants, avibactam, is now available in the clinic in partnership with ceftazidime. Here, we explored the activity of avibactam against a variety of characterized isogenic laboratory constructs of \u03b2-lactamase inhibitor-resistant variants of the class A enzyme SHV (M69I\/L\/V, S130G, K234R, R244S, and N276D). We discovered that the S130G variant of SHV-1 shows the most significant resistance to inhibition by avibactam, based on both microbiological and biochemical characterizations. Using a constant concentration of 4 mg\/liter of avibactam as a \u03b2-lactamase inhibitor in combination with ampicillin, the MIC increased from 1 mg\/liter for\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>SHV-1<\/jats:sub>\n            to 256 mg\/liter for\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>SHV S130G<\/jats:sub>\n            expressed in\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            DH10B. At steady state, the\n            <jats:italic>k<\/jats:italic>\n            <jats:sub>2<\/jats:sub>\n            \/\n            <jats:italic>K<\/jats:italic>\n            value of the S130G variant when inactivated by avibactam was 1.3 M\n            <jats:sup>\u22121<\/jats:sup>\n            s\n            <jats:sup>\u22121<\/jats:sup>\n            , versus 60,300 M\n            <jats:sup>\u22121<\/jats:sup>\n            s\n            <jats:sup>\u22121<\/jats:sup>\n            for the SHV-1 \u03b2-lactamase. Under timed inactivation conditions, we found that an approximately 1,700-fold-higher avibactam concentration was required to inhibit SHV S130G than the concentration that inhibited SHV-1. Molecular modeling suggested that the positioning of amino acids in the active site of SHV may result in an alternative pathway of inactivation when complexed with avibactam, compared to the structure of CTX-M-15\u2013avibactam, and that S130 plays a role in the acylation of avibactam as a general acid\/base. In addition, S130 may play a role in recyclization. As a result, we advance that the lack of a hydroxyl group at position 130 in the S130G variant of SHV-1 substantially slows carbamylation of the \u03b2-lactamase by avibactam by (i) removing an important proton acceptor and donator in catalysis and (ii) decreasing the number of H bonds. In addition, recyclization is most likely also slow due to the lack of a general base to initiate the process. Considering other inhibitor-resistant mechanisms among class A \u03b2-lactamases, S130 may be the most important amino acid for the inhibition of class A \u03b2-lactamases, perhaps even for the novel diazabicyclooctane class of \u03b2-lactamase inhibitors.\n          <\/jats:p>","DOI":"10.1128\/aac.04405-14","type":"journal-article","created":{"date-parts":[[2015,2,18]],"date-time":"2015-02-18T03:01:46Z","timestamp":1424228506000},"page":"3700-3709","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":80,"title":["Avibactam and Inhibitor-Resistant SHV \u03b2-Lactamases"],"prefix":"10.1128","volume":"59","author":[{"given":"Marisa L.","family":"Winkler","sequence":"first","affiliation":[{"name":"Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA"},{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina M.","family":"Papp-Wallace","sequence":"additional","affiliation":[{"name":"Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena A.","family":"Taracila","sequence":"additional","affiliation":[{"name":"Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA"},{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.017"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2760269"},{"key":"e_1_3_2_4_2","volume-title":"\u03b2-Lactamase classification and amino acid sequences for TEM, SHV and OXA extended-spectrum and inhibitor resistant enzymes","author":"Bush K","year":"2015","unstructured":"Bush K, Palzkill T, Jacoby G. 2015. \u03b2-Lactamase classification and amino acid sequences for TEM, SHV and OXA extended-spectrum and inhibitor resistant enzymes. Lahey Clinic, Burlington, MA. http:\/\/www.lahey.org\/Studies\/. Accessed 1 July 2014."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00037-09"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi060990m"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501251200"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306059200"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0487903"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0502700"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi700581q"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm301490d"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9003292"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207271200"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M603222200"},{"key":"e_1_3_2_16_2","volume-title":"FDA approves new antibacterial drug Avycaz","author":"U.S. Food and Drug Administration","year":"2015","unstructured":"U.S. Food and Drug Administration. 2015. FDA approves new antibacterial drug Avycaz. U.S. FDA, Silver Spring, MD."},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.485979"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02247-12"},{"key":"e_1_3_2_19_2","volume-title":"Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement","author":"Clinical and Laboratory Standards Institute","year":"2014","unstructured":"Clinical and Laboratory Standards Institute. 2014. Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA."},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1042\/bj3330395","article-title":"Kinetic analysis of an inhibitor-resistant variant of the OHIO-1 \u03b2-lactamase, an SHV-family class A enzyme","volume":"333","author":"Lin S","year":"1998","unstructured":"Lin S, Thomas M, Shlaes DM, Rudin SD, Knox JR, Anderson V, Bonomo RA. 1998. Kinetic analysis of an inhibitor-resistant variant of the OHIO-1 \u03b2-lactamase, an SHV-family class A enzyme. Biochem J 333:395\u2013400.","journal-title":"Biochem J"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02625-14"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05769-11"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi700792a"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.5.1747"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja051592u"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M313143200"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi1015088"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/359700a0"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja3073676"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0259640"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M505333200"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja027704o"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi500589x"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.612"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00178-11"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.04405-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.04405-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:54:04Z","timestamp":1645484044000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.04405-14"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7]]},"references-count":34,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2015,7]]}},"alternative-id":["10.1128\/AAC.04405-14"],"URL":"https:\/\/doi.org\/10.1128\/aac.04405-14","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,7]]},"assertion":[{"value":"2014-09-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-01-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-06-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}