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The development of inhibitors for drug\u2010resistant \u03b2\u2010lactamase enzymes is vital to combat this rapidly escalating problem. Recently, the U.S. Food and Drug Administration approved a non\u2010\u03b2\u2010lactam inhibitor called avibactam for the treatment of complicated intra\u2010abdominal and urinary tract infections caused by drug\u2010resistant Gram\u2010negative bacteria. This work sheds light on the molecular origin of the inhibitory effect of avibactam against the drug\u2010resistant CTX\u2010M variant of class\u2005A \u03b2\u2010lactamases. In particular, we probed the structural evolution, dynamics features, and energetics along the acylation and deacylation reaction pathways through enhanced sampling molecular dynamics methods and free\u2010energy calculations. We scrutinized the roles of active site residues, the nature of the carbamoyl linkage formed in the inhibitor\u2013enzyme covalent intermediate, and other structural features of the inhibitor molecule. By unraveling the reasons behind the inhibition of all the deacylation routes, we can explain various experimental structural and kinetics data, and propose a way to design new inhibitors based on the \u03b2\u2010lactam framework.<\/jats:p>","DOI":"10.1002\/chem.202001261","type":"journal-article","created":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T06:59:05Z","timestamp":1586847545000},"page":"9639-9651","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Elucidating the Molecular Basis of Avibactam\u2010Mediated Inhibition of Class\u2005A \u03b2\u2010Lactamases"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3498-0425","authenticated-orcid":false,"given":"Chandan Kumar","family":"Das","sequence":"first","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Kanpur  Kanpur 208016 India"},{"name":"Current Address: Lehrstuhl f\u00fcr Theoretische Chemie Ruhr Universit\u00e4t Bochum  44780 Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8650-8873","authenticated-orcid":false,"given":"Nisanth N.","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Kanpur  Kanpur 208016 India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,9]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc8892"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2165\/11318430-000000000-00000"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.6.1211"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2010.09.006"},{"key":"e_1_2_7_5_1","unstructured":"WHO Antimicrobial resistance: global report on surveillance 2014 WHO Press World Health Organization Geneva 2014 http:\/\/www.who.int\/drugresistance\/documents\/surveillancereport\/en\/(accessed Oct 2017)."},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00037-09"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408410902733979"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2011.07.026"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-013-0013-7"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc-2016-0078"},{"key":"e_1_2_7_11_1","first-page":"39","volume":"62","author":"Alatoom A.","year":"2017","journal-title":"J. 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