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Knowledge of the interactions of avibactam, a diazabicyclooctane with different \u03b2-lactamases, is required to anticipate future resistance threats. FOX family \u03b2-lactamases possess unique hydrolytic properties with a broadened substrate profile to include cephamycins, partly as a result of an isoleucine at position 346, instead of the conserved asparagine found in most AmpCs. Interestingly, a single amino acid substitution at N346 in the\n            <jats:named-content content-type=\"genus-species\">Citrobacter<\/jats:named-content>\n            AmpC is implicated in resistance to the aztreonam-avibactam combination. In order to understand how diverse active-site topologies affect avibactam inhibition, we tested a panel of clinical\n            <jats:named-content content-type=\"genus-species\">Enterobacteriaceae<\/jats:named-content>\n            isolates producing\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>FOX<\/jats:sub>\n            using ceftazidime-avibactam, determined the biochemical parameters for inhibition using the FOX-4 variant, and probed the atomic structure of avibactam with FOX-4. Avibactam restored susceptibility to ceftazidime for most isolates producing\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>FOX<\/jats:sub>\n            ; two isolates, one expressing\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>FOX-4<\/jats:sub>\n            and the other producing\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>FOX-5<\/jats:sub>\n            , displayed an MIC of 16 \u03bcg\/ml for the combination. FOX-4 possessed a\n            <jats:italic>k<\/jats:italic>\n            <jats:sub>2<\/jats:sub>\n            \/\n            <jats:italic>K<\/jats:italic>\n            value of 1,800 \u00b1 100 M\n            <jats:sup>\u22121<\/jats:sup>\n            \u00b7 s\n            <jats:sup>\u22121<\/jats:sup>\n            and an off rate (\n            <jats:italic>k<\/jats:italic>\n            <jats:sub>off<\/jats:sub>\n            ) of 0.0013 \u00b1 0.0003 s\n            <jats:sup>\u22121<\/jats:sup>\n            . Mass spectrometry showed that the FOX-4\u2013avibactam complex did not undergo chemical modification for 24 h. Analysis of the crystal structure of FOX-4 with avibactam at a 1.5-\u00c5 resolution revealed a unique characteristic of this AmpC \u03b2-lactamase. Unlike in the\n            <jats:named-content content-type=\"genus-species\">Pseudomonas<\/jats:named-content>\n            -derived cephalosporinase 1 (PDC-1)\u2013avibactam crystal structure, interactions (e.g., hydrogen bonding) between avibactam and position I346 in FOX-4 are not evident. Furthermore, another residue is not observed to be close enough to compensate for the loss of these critical hydrogen-bonding interactions. This observation supports findings from the inhibition analysis of FOX-4; FOX-4 possessed the highest\n            <jats:italic>\n              K\n              <jats:sub>d<\/jats:sub>\n            <\/jats:italic>\n            (dissociation constant) value (1,600 nM) for avibactam compared to other AmpCs (7 to 660 nM). Medicinal chemists must consider the properties of extended-spectrum AmpCs, such as the FOX \u03b2-lactamases, for the design of future diazabicyclooctanes.\n          <\/jats:p>","DOI":"10.1128\/aac.02371-17","type":"journal-article","created":{"date-parts":[[2018,2,10]],"date-time":"2018-02-10T12:57:02Z","timestamp":1518267422000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Probing the Mechanism of Inactivation of the FOX-4 Cephamycinase by Avibactam"],"prefix":"10.1128","volume":"62","author":[{"given":"Michiyoshi","family":"Nukaga","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Josai International University, Togane City, Chiba, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krisztina M.","family":"Papp-Wallace","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, Ohio, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyuji","family":"Hoshino","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott T.","family":"Lefurgy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Hofstra University, Hempstead, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher R.","family":"Bethel","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa D.","family":"Barnes","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, Ohio, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elise T.","family":"Zeiser","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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