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dc.contributor.author
Ghiglione, Barbara
dc.contributor.author
Rodríguez, María Margarita
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Curto, Lucrecia María
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Brunetti, Florencia Lourdes
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Dropa, Milena
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Bonomo, Robert A.
dc.contributor.author
Power, Pablo
dc.contributor.author
Gutkind, Gabriel Osvaldo
dc.date.available
2020-03-16T22:00:35Z
dc.date.issued
2018-06
dc.identifier.citation
Ghiglione, Barbara; Rodríguez, María Margarita; Curto, Lucrecia María; Brunetti, Florencia Lourdes; Dropa, Milena; et al.; Defining substrate specificity in the ctx-m family: The role of asp240 in ceftazidime hydrolysis; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 62; 6; 6-2018; 1-13
dc.identifier.issn
0066-4804
dc.identifier.uri
http://hdl.handle.net/11336/99746
dc.description.abstract
The natural diversification of CTX-M -lactamases led to the emergence of Asp240Gly variants in the clinic that confer reduced susceptibility to ceftazidime (CAZ). In this study, we compared the impact of this substitution on CAZ and ceftazidime-avibactam (CZA) MICs against isogenic Escherichia coli strains with different porin deficiencies. Our results show a noticeable increase in CAZ resistance in clones expressing Asp240Gly-harboring CTX-M when combined with OmpF porin deficiency. Kinetic analysis revealed that the kcat/Km for CAZ was 5- to 15-fold higher for all Asp240Gly variants but remained 200- to 725-fold lower than that for cefotaxime (CTX). In vitro selection of CAZ-resistant clones yielded nonsusceptible CTX-M producers (MIC of 16 g/ml) only after overnight incubation; the addition of avibactam (AVI) decreased MICs to a susceptible range against these variants. In contrast, the use of CZA as a selective agent did not yield resistant clones. AVI inactivated both CTX-M-12 and CTX-M-96, with an apparent inhibition constant comparable to that of SHV-2 and 1,000-fold greater than that of PER-2 and CMY-2, and k2/K for CTX-M-12 was 24- and 35-fold higher than that for CTX-M-96 and CTX-M-15, respectively. Molecular modeling suggests that AVI interacts similarly with CTX-M-96 and CTX-M-15. We conclude that the impact of Asp240Gly in resistance may arise when other mechanisms are also present (i.e., OmpF deficiency). Additionally, CAZ selection could favor the emergence of CAZ-resistant subpopulations. These results define the role of Asp240 and the impact of the -Gly substitution and allow us to hypothesize that the use of CZA is an effective preventive strategy to delay the development of resistance in this family of extended-spectrum -lactamases.
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
ASP240GLY
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AVIBACTAM
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CEFOTAXIME
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CEFTAZIDIMASE
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CEFTAZIDIME
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CEFTAZIDIME-AVIBACTAM
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CTX-M-96
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OMPF
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Bioquímica y Biología Molecular
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Defining substrate specificity in the ctx-m family: The role of asp240 in ceftazidime hydrolysis
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-10-21T19:01:07Z
dc.journal.volume
62
dc.journal.number
6
dc.journal.pagination
1-13
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Ghiglione, Barbara. 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: Rodríguez, María Margarita. 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
dc.description.fil
Fil: Brunetti, Florencia Lourdes. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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Fil: Dropa, Milena. Universidade de Sao Paulo; Brasil
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Fil: Bonomo, Robert A.. Case Western Reserve University School of Medicine; Estados Unidos. Louis Stokes Cleveland VA Medical Center; 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.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/url/https://aac.asm.org/content/62/6/e00116-18.long
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1128/AAC.00116-18
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