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Artículo

Structural and biochemical characterization of the novel CTXM-151 extended-spectrum β-lactamase and its inhibition by avibactam

Ghiglione, BarbaraIcon ; Rodríguez, María MargaritaIcon ; Brunetti, Florencia LourdesIcon ; Papp Wallace, Krisztina M.; Yoshizumi, Ayumi; Ishii, Yoshikazu; Bonomo, Robert A.; Gutkind, Gabriel OsvaldoIcon ; Klinke, SebastianIcon ; Power, PabloIcon
Fecha de publicación: 04/2021
Editorial: American Society for Microbiology
Revista: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Biología Celular, Microbiología

Resumen

The diazabicyclooctane (DBO) inhibitor avibactam (AVI) reversibly inactivates most serine β-lactamases, including the CTX-M β-lactamases. Currently, more than 230 unique CTX-M members distributed in five clusters with less than 5% amino acid sequence divergence within each group have been described. Recently, a variant named CTX-M-151 was isolated from a Salmonella enterica subsp. enterica serovar Choleraesuis strain in Japan. This variant possesses a low degree of amino acid identity with the other CTX-Ms (63.2% to 69.7% with respect to the mature proteins), and thus it may represent a new subgroup within the family. CTX-M-151 hydrolyzes ceftriaxone better than ceftazidime (kcat/Km values 6,000-fold higher), as observed with CTX-Ms. CTX-M-151 is well inhibited by mechanism-based inhibitors like clavulanic acid (inactivation rate [kinact]/inhibition constant [Ki] = 0.15μM-1 · s-1). For AVI, the apparent inhibition constant (Ki app), 0.4mM, was comparable to that of KPC-2; the acylation rate (k2/K) (37,000 M-1 · s-1) was lower than that for CTX-M-15, while the deacylation rate (koff) (0.0015 s21) was 2- to 14-fold higher than those of other class A β-lactamases. The structure of the CTX-M-151/AVI complex (1.32 Å) reveals that AVI adopts a chair conformation with hydrogen bonds between the AVI carbamate and Ser70 and Ser237 at the oxyanion hole. Upon acylation, the side chain of Lys73 points toward Ser130, which is associated with the protonation of Glu166, supporting the role of Lys73 in the proton relay pathway and Glu166 as the general base in deacylation. To our knowledge, this is the first chromosomally encoded CTX-M in Salmonella Choleraesuis that shows similar hydrolytic preference toward cefotaxime (CTX) and ceftriaxone (CRO) to that toward ceftazidime (CAZ).
Palabras clave: CEFOTAXIMASE , DBO , ESBL , PHYLOGENY , SALMONELLA CHOLERAESUIS , X-RAY CRYSTALLOGRAPHY
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/140876
URL: https://aac.asm.org/content/65/4/e01757-20
DOI: http://dx.doi.org/10.1128/aac.01757-20
Colecciones
Articulos(IIBBA)
Articulos de INST.DE INVEST.BIOQUIMICAS DE BS.AS(I)
Articulos(OCA HOUSSAY)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Citación
Ghiglione, Barbara; Rodríguez, María Margarita; Brunetti, Florencia Lourdes; Papp Wallace, Krisztina M.; Yoshizumi, Ayumi; et al.; Structural and biochemical characterization of the novel CTXM-151 extended-spectrum β-lactamase and its inhibition by avibactam; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 65; 4; 4-2021; 1-14
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