Artículo
Structural insights into the inhibition of the extended-spectrum -lactamase PER-2 by avibactam
Ruggiero, Melina
; Papp Wallace, Krisztina M.; Brunetti, Florencia Lourdes
; Barnes, Melissa D.; Bonomo, Robert A.; Gutkind, Gabriel Osvaldo
; Klinke, Sebastian
; Power, Pablo
Fecha de publicación:
08/2019
Editorial:
American Society for Microbiology
Revista:
Antimicrobial Agents and Chemotherapy
ISSN:
0066-4804
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
The diazabicyclooctane (DBO) avibactam (AVI) reversibly inactivates most serine-lactamases. Previous investigations showed that inhibition constants of AVI toward class A PER-2 are reminiscent of values observed for class C and D -lactamases (i.e., k2/K of 103 M1 s1) but lower than other class A -lactamases (i.e., k2/K 104 to 105 M1 s1). Herein, biochemical and structural studies were conducted with PER-2 and AVI to explore these differences. Furthermore, biochemical studies on Arg220 and Thr237 variants with AVI were conducted to gain deeper insight into the mechanism of PER-2 inactivation. The main biochemical and structural observations revealed the following: (i) both amino-acid substitutions in Arg220 and the rich hydrophobic content in the active site hinder the binding of catalytic waters and acylation, impairing AVI inhibition; (ii) movement of Ser130 upon binding of AVI favors the formation of a hydrogen bond with the sulfate group of AVI; and (iii) the Thr237Ala substitution alters the AVI inhibition constants. The acylation constant (k2/K) of PER-2 by AVI is primarily influenced by stabilizing hydrogen bonds involving AVI and important residues such as Thr237 and Arg220. (Variants in Arg220 demonstrate a dramatic reduction in k2/K.) We also observed that displacement of Ser130 side chain impairs AVI acylation, an observation not made in other extended-spectrum -lactamases (ESBLs). Comparatively, relebactam combined with a -lactam is more potent against Escherichia coli producing PER-2 variants than -lactam–AVI combinations. Our findings provide a rationale for evaluating the utility of the currently available DBO inhibitors against unique ESBLs like PER-2 and anticipate the effectiveness of these inhibitors toward variants that may eventually be selected upon AVI usage.
Palabras clave:
LACTAM
,
LACTAMASE
,
LACTAMASE INHIBITOR
,
DBO
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(IIBBA)
Articulos de INST.DE INVEST.BIOQUIMICAS DE BS.AS(I)
Articulos de INST.DE INVEST.BIOQUIMICAS DE BS.AS(I)
Articulos(OCA HOUSSAY)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Citación
Ruggiero, Melina; Papp Wallace, Krisztina M.; Brunetti, Florencia Lourdes; Barnes, Melissa D.; Bonomo, Robert A.; et al.; Structural insights into the inhibition of the extended-spectrum -lactamase PER-2 by avibactam; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 63; 9; 8-2019; 1-12
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