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Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis
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| Zeitschriftentitel: | Antimicrobial Agents and Chemotherapy |
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| Personen und Körperschaften: | , , , , , , , |
| In: | Antimicrobial Agents and Chemotherapy, 62, 2018, 6 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
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| Schlagwörter: |
| author_facet |
Ghiglione, Barbara Rodríguez, María Margarita Curto, Lucrecia Brunetti, Florencia Dropa, Milena Bonomo, Robert A. Power, Pablo Gutkind, Gabriel Ghiglione, Barbara Rodríguez, María Margarita Curto, Lucrecia Brunetti, Florencia Dropa, Milena Bonomo, Robert A. Power, Pablo Gutkind, Gabriel |
|---|---|
| author |
Ghiglione, Barbara Rodríguez, María Margarita Curto, Lucrecia Brunetti, Florencia Dropa, Milena Bonomo, Robert A. Power, Pablo Gutkind, Gabriel |
| spellingShingle |
Ghiglione, Barbara Rodríguez, María Margarita Curto, Lucrecia Brunetti, Florencia Dropa, Milena Bonomo, Robert A. Power, Pablo Gutkind, Gabriel Antimicrobial Agents and Chemotherapy Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis Infectious Diseases Pharmacology (medical) Pharmacology |
| author_sort |
ghiglione, barbara |
| spelling |
Ghiglione, Barbara Rodríguez, María Margarita Curto, Lucrecia Brunetti, Florencia Dropa, Milena Bonomo, Robert A. Power, Pablo Gutkind, Gabriel 0066-4804 1098-6596 American Society for Microbiology Infectious Diseases Pharmacology (medical) Pharmacology http://dx.doi.org/10.1128/aac.00116-18 <jats:title>ABSTRACT</jats:title> <jats:p> The natural diversification of CTX-M β-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 <jats:named-content content-type="genus-species">Escherichia coli</jats:named-content> 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 <jats:italic>k</jats:italic> <jats:sub>cat</jats:sub> / <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> for CAZ was 5- to 15-fold higher for all Asp240Gly variants but remained 200- to 725-fold lower than that for cefotaxime (CTX). <jats:italic>In vitro</jats:italic> selection of CAZ-resistant clones yielded nonsusceptible CTX-M producers (MIC of >16 μg/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 <jats:italic> k <jats:sub>2</jats:sub> /K </jats:italic> 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 β-lactamases. </jats:p> Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis Antimicrobial Agents and Chemotherapy |
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| title |
Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_unstemmed |
Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_full |
Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_fullStr |
Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_full_unstemmed |
Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_short |
Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_sort |
defining substrate specificity in the ctx-m family: the role of asp240 in ceftazidime hydrolysis |
| topic |
Infectious Diseases Pharmacology (medical) Pharmacology |
| url |
http://dx.doi.org/10.1128/aac.00116-18 |
| publishDate |
2018 |
| physical |
|
| description |
<jats:title>ABSTRACT</jats:title>
<jats:p>
The natural diversification of CTX-M β-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
<jats:named-content content-type="genus-species">Escherichia coli</jats:named-content>
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
<jats:italic>k</jats:italic>
<jats:sub>cat</jats:sub>
/
<jats:italic>
K
<jats:sub>m</jats:sub>
</jats:italic>
for CAZ was 5- to 15-fold higher for all Asp240Gly variants but remained 200- to 725-fold lower than that for cefotaxime (CTX).
<jats:italic>In vitro</jats:italic>
selection of CAZ-resistant clones yielded nonsusceptible CTX-M producers (MIC of >16 μg/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
<jats:italic>
k
<jats:sub>2</jats:sub>
/K
</jats:italic>
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 β-lactamases.
</jats:p> |
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| author | Ghiglione, Barbara, Rodríguez, María Margarita, Curto, Lucrecia, Brunetti, Florencia, Dropa, Milena, Bonomo, Robert A., Power, Pablo, Gutkind, Gabriel |
| author_facet | Ghiglione, Barbara, Rodríguez, María Margarita, Curto, Lucrecia, Brunetti, Florencia, Dropa, Milena, Bonomo, Robert A., Power, Pablo, Gutkind, Gabriel, Ghiglione, Barbara, Rodríguez, María Margarita, Curto, Lucrecia, Brunetti, Florencia, Dropa, Milena, Bonomo, Robert A., Power, Pablo, Gutkind, Gabriel |
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| description | <jats:title>ABSTRACT</jats:title> <jats:p> The natural diversification of CTX-M β-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 <jats:named-content content-type="genus-species">Escherichia coli</jats:named-content> 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 <jats:italic>k</jats:italic> <jats:sub>cat</jats:sub> / <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> for CAZ was 5- to 15-fold higher for all Asp240Gly variants but remained 200- to 725-fold lower than that for cefotaxime (CTX). <jats:italic>In vitro</jats:italic> selection of CAZ-resistant clones yielded nonsusceptible CTX-M producers (MIC of >16 μg/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 <jats:italic> k <jats:sub>2</jats:sub> /K </jats:italic> 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 β-lactamases. </jats:p> |
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| spelling | Ghiglione, Barbara Rodríguez, María Margarita Curto, Lucrecia Brunetti, Florencia Dropa, Milena Bonomo, Robert A. Power, Pablo Gutkind, Gabriel 0066-4804 1098-6596 American Society for Microbiology Infectious Diseases Pharmacology (medical) Pharmacology http://dx.doi.org/10.1128/aac.00116-18 <jats:title>ABSTRACT</jats:title> <jats:p> The natural diversification of CTX-M β-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 <jats:named-content content-type="genus-species">Escherichia coli</jats:named-content> 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 <jats:italic>k</jats:italic> <jats:sub>cat</jats:sub> / <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> for CAZ was 5- to 15-fold higher for all Asp240Gly variants but remained 200- to 725-fold lower than that for cefotaxime (CTX). <jats:italic>In vitro</jats:italic> selection of CAZ-resistant clones yielded nonsusceptible CTX-M producers (MIC of >16 μg/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 <jats:italic> k <jats:sub>2</jats:sub> /K </jats:italic> 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 β-lactamases. </jats:p> Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis Antimicrobial Agents and Chemotherapy |
| spellingShingle | Ghiglione, Barbara, Rodríguez, María Margarita, Curto, Lucrecia, Brunetti, Florencia, Dropa, Milena, Bonomo, Robert A., Power, Pablo, Gutkind, Gabriel, Antimicrobial Agents and Chemotherapy, Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis, Infectious Diseases, Pharmacology (medical), Pharmacology |
| title | Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_full | Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_fullStr | Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_full_unstemmed | Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_short | Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| title_sort | defining substrate specificity in the ctx-m family: the role of asp240 in ceftazidime hydrolysis |
| title_unstemmed | Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis |
| topic | Infectious Diseases, Pharmacology (medical), Pharmacology |
| url | http://dx.doi.org/10.1128/aac.00116-18 |