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dc.contributor.author Ruggiero, Melina
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
dc.contributor.author Bonomo, Robert A.
dc.contributor.author Power, Pablo
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
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
dc.subject.classification Ciencias Biológicas
dc.subject.classification CIENCIAS NATURALES Y EXACTAS
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
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
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
dc.conicet.fuente individual


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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)