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dc.contributor.author
Ruggiero, Melina
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dc.contributor.author
Papp Wallace, Krisztina M.
dc.contributor.author
Taracila, Magdalena A.
dc.contributor.author
Mojica, Maria F.
dc.contributor.author
Bethel, Christopher R.
dc.contributor.author
Rudin, Susan D.
dc.contributor.author
Zeiser, Elise T.
dc.contributor.author
Gutkind, Gabriel Osvaldo
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dc.contributor.author
Bonomo, Robert A.
dc.contributor.author
Power, Pablo
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dc.date.available
2018-06-15T18:07:33Z
dc.date.issued
2017-06
dc.identifier.citation
Ruggiero, Melina; Papp Wallace, Krisztina M.; Taracila, Magdalena A.; Mojica, Maria F.; Bethel, Christopher R.; et al.; Exploring the landscape of diazabicyclooctane (DBO) inhibition: Avibactam inactivation of PER-2 β-Lactamase; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 61; 6; 6-2017
dc.identifier.issn
0066-4804
dc.identifier.uri
http://hdl.handle.net/11336/48832
dc.description.abstract
PER β -lactamases are an emerging family of extended-spectrum β -lactamases (ESBL) found in Gram-negative bacteria. PER β -lactamases are unique among class A enzymes as they possess an inverted omega (?) loop and extended B3 β -strand. These singular structural features are hypothesized to contribute to their hydrolytic profile against oxyimino-cephalosporins (e.g., cefotaxime and ceftazidime). Here, we tested the ability of avibactam (AVI), a novel non- β -lactam β -lactamase inhibitor to inactivate PER-2. Interestingly, the PER-2 inhibition constants (i.e., k2/K = 2 × 103 ±0.1 × 103 M-1 s-1, where k2 is the rate constant for acylation (carbamylation) and K is the equilibrium constant) that were obtained when AVI was tested were reminiscent of values observed testing the inhibition by AVI of class C and D β -lactamases (i.e., k2/K range of =103 M-1s-1) and not class A β -lactamases (i.e., k2/K range, 104 to 105 M-1s-1). Once AVI was bound, a stable complex with PER-2 was observed via mass spectrometry (e.g., 31,389 ± 3 atomic mass units [amu] ¡ 31,604 ± 3 amu for 24 h). Molecular modeling of PER-2 with AVI showed that the carbonyl of AVI was located in the oxyanion hole of the β -lactamase and that the sulfate of AVI formed interactions with the β-lactam carboxylate binding site of the PER-2 β -lactamase (R220 and T237). However, hydrophobic patches near the PER-2 active site (by Ser70 and B3-B4 β -strands) were observed and may affect the binding of necessary catalytic water molecules, thus slowing acylation (k2/K) of AVI onto PER-2. Similar electrostatics and hydrophobicity of the active site were also observed between OXA-48 and PER-2, while CTX-M-15 was more hydrophilic. To demonstrate the ability of AVI to overcome the enhanced cephalosporinase activity of PER-2 β-lactamase, we tested different β -lactam-AVI combinations. By lowering MICs to ≤2 mg/liter, the ceftaroline-AVI combination could represent a favorable therapeutic option against Enterobacteriaceae expressing blaPER-2. Our studies define the inactivation of the PER-2 ESBL by AVI and suggest that the biophysical properties of the active site contribute to determining the efficiency of inactivation.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society for Microbiology
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Avibactam
dc.subject
Beta-Lactamases
dc.subject
Beta-Lactams
dc.subject.classification
Otras Ciencias Biológicas
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Exploring the landscape of diazabicyclooctane (DBO) inhibition: Avibactam inactivation of PER-2 β-Lactamase
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-06-07T14:22:08Z
dc.journal.volume
61
dc.journal.number
6
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Washington
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: Papp Wallace, Krisztina M.. Louis Stokes Cleveland Department of Veterans Affairs; Estados Unidos. Case Western Reserve University; Estados Unidos
dc.description.fil
Fil: Taracila, Magdalena A.. Louis Stokes Cleveland Department of Veterans Affairs; Estados Unidos. Case Western Reserve University; Estados Unidos
dc.description.fil
Fil: Mojica, Maria F.. Louis Stokes Cleveland Department of Veterans Affairs; Estados Unidos
dc.description.fil
Fil: Bethel, Christopher R.. Louis Stokes Cleveland Department of Veterans Affairs; Estados Unidos
dc.description.fil
Fil: Rudin, Susan D.. Louis Stokes Cleveland Department of Veterans Affairs; Estados Unidos. Case Western Reserve University; Estados Unidos
dc.description.fil
Fil: Zeiser, Elise T.. Louis Stokes Cleveland Department of Veterans Affairs; Estados Unidos
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.description.fil
Fil: Bonomo, Robert A.. Louis Stokes Cleveland Department of Veterans Affairs; Estados Unidos. Case Western Reserve University; Estados Unidos
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.journal.title
Antimicrobial Agents and Chemotherapy
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1128/AAC.02476-16
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://aac.asm.org/content/61/6/e02476-16
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