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Recent reports have described ceftazidime-\/avibactam-resistant isolates producing CTX-M variants with different amino acid substitutions (e.g., P167S, L169Q, and S130G). Relebactam (REL) combined with imipenem has proved very effective against Enterobacterales producing ESBLs, serine-carbapenemases, and AmpCs. Herein, we evaluated the inhibitory efficacy of REL against CTX-M-96, a CTX-M-15-type variant. The CTX-M-96 structure was obtained in complex with REL at 1.03 \u00c5 resolution (PDB 8EHH). REL was covalently bound to the S70-O\u03b3 atom upon cleavage of the C7-N6 bond. Compared with apo CTX-M-96, binding of REL forces a slight displacement of the deacylating water inwards the active site (0.81 \u00c5), making the E166 and N170 side chains shift to create a proper hydrogen bonding network. Binding of REL also disturbs the hydrophobic patch formed by Y105, P107, and Y129, likely due to the piperidine ring of REL that creates clashes with these residues. Also, a remarkable change in the positioning of the N104 sidechain is also affected by the piperidine ring. Therefore, differences in the kinetic behavior of REL against class A \u03b2-lactamases seem to rely, at least in part, on differences in the residues being involved in the association and stabilization of the inhibitor before hydrolysis. Our data provide the biochemical and structural basis for REL effectiveness against CTX-M-producing Gram-negative pathogens and essential details for further DBO design. Imipenem\/REL remains an important choice for dealing with isolates co-producing CTX-M with other \u03b2-lactamases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01721-23","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T13:20:28Z","timestamp":1720704028000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Crystal structure of the class A extended-spectrum \u03b2-lactamase CTX-M-96 in complex with relebactam at 1.03 Angstrom resolution"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1723-5135","authenticated-orcid":true,"given":"Barbara","family":"Ghiglione","sequence":"first","affiliation":[{"name":"Universidad de Buenos Aires, Facultad de Farmacia y Bioqu\u00edmica, Instituto de Investigaciones en Bacteriolog\u00eda y Virolog\u00eda Molecular (IBaViM), Buenos Aires, Argentina"},{"name":"Consejo Nacional de 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