Crystal structure of the class A extended-spectrum β-lactamase CTX-M-96 in complex with relebactam at 1.03 Angstrom resolution.

Autor:	Ghiglione B; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Rodríguez MM; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Penzotti P; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Buenos Aires, Argentina., Bethel CR; Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA., Gutkind G; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Bonomo RA; Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.; Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.; Departments of Pharmacology, Biochemistry, Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA.; Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA.; Clinician Scientist Investigator, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA., Klinke S; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.; Fundación Instituto Leloir, IIBBA-CONICET, and Plataforma Argentina de Biología Estructural y Metabolómica PLABEM, Buenos Aires, Argentin., Power P; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Aug 07; Vol. 68 (8), pp. e0172123. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.1128/aac.01721-23
Abstrakt:	The use of β-lactam/β-lactamase inhibitors constitutes an important strategy to counteract β-lactamases in multidrug-resistant (MDR) Gram-negative bacteria. 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 Å resolution (PDB 8EHH). REL was covalently bound to the S70-Oγ 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 Å), 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 β-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 β-lactamases. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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