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dc.contributor.author
Ruggiero, Melina
dc.contributor.author
Curto, Lucrecia María
dc.contributor.author
Brunetti, Florencia Lourdes
dc.contributor.author
Sauvage, Eric
dc.contributor.author
Galleni, Moreno
dc.contributor.author
Power, Pablo
dc.contributor.author
Gutkind, Gabriel Osvaldo
dc.date.available
2018-06-04T20:31:39Z
dc.date.issued
2017-06
dc.identifier.citation
Ruggiero, Melina; Curto, Lucrecia María; Brunetti, Florencia Lourdes; Sauvage, Eric; Galleni, Moreno; et al.; Impact of mutations at Arg220 and Thr237 in PER-2 β-Lactamase on conformation, activity, and susceptibility to inhibitors; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 61; 6; 6-2017; 1-29; e02193
dc.identifier.issn
0066-4804
dc.identifier.uri
http://hdl.handle.net/11336/47225
dc.description.abstract
PER-2 accounts for up to 10% of oxyimino-cephalosporin resistance in Klebsiella pneumoniae and Escherichia coli in Argentina and hydrolyzes both cefotaxime and ceftazidime with high catalytic efficiencies (kcat/Km). Through crystallographic analyses, we recently proposed the existence of a hydrogen bond network connecting Ser70-Gln69-oxyanion water-Thr237-Arg220 that might be important for the activity and inhibition of the enzyme. Mutations at Arg244 in most class A β -lactamases (such as TEM and SHV) reduce susceptibility to mechanism-based inactivators, and Arg220 in PER β -lactamases is equivalent to Arg244. Alterations in the hydrogen bond network of the active site in PER-2, through modifications in key residues such as Arg220 and (to a much lesser extent) Thr237, dramatically impact the overall susceptibility to inactivation, with up to 300-And 500-fold reductions in the rate constant of inactivation (kinact)/Kivalues for clavulanic acid and tazobactam, respectively. Hydrolysis on cephalosporins and aztreonam was also affected, although to different extents compared to with wild-Type PER-2; for cefepime, only an Arg220Gly mutation resulted in a strong reduction in the catalytic efficiency. Mutations at Arg220 entail modifications in the catalytic activity of PER-2 and probably local perturbations in the protein, but not global conformational changes. Therefore, the apparent structural stability of the mutants suggests that these enzymes could be possibly selected in vivo.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society for Microbiology
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Arg220
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Cefotaximase
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Ceftazidimase
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Esbl
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Inhibitor Resistant
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Mechanism-Based Inhibitor
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Thr237
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Otras Ciencias Biológicas
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Impact of mutations at Arg220 and Thr237 in PER-2 β-Lactamase on conformation, activity, and susceptibility to inhibitors
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-06-04T17:02:05Z
dc.journal.volume
61
dc.journal.number
6
dc.journal.pagination
1-29; e02193
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Washington DC
dc.description.fil
Fil: Ruggiero, Melina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
dc.description.fil
Fil: Curto, Lucrecia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina
dc.description.fil
Fil: Brunetti, Florencia Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
dc.description.fil
Fil: Sauvage, Eric. Université de Liège; Bélgica
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Fil: Galleni, Moreno. Université de Liège; Bélgica
dc.description.fil
Fil: Power, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
dc.description.fil
Fil: Gutkind, Gabriel Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
dc.journal.title
Antimicrobial Agents and Chemotherapy
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1128/AAC.02193-16
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/aac.asm.org/content/61/6/e02193-16


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    Articulos de INST.DE QUIMICA Y FISICO-QUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"

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