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The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States

Tebipenem-pivoxil hydrobromide, an orally bioavailable carbapenem, is currently in clinical development for the treatment of extended-spectrum β-lactamase- and AmpC-producing Enterobacterales. Previously, tebipenem was found to possess antimicrobial activity against the biothreat pathogens, Burkhold...

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Autores principales: Becka, Scott A., Zeiser, Elise T., LiPuma, John J., Papp-Wallace, Krisztina M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137479/
https://www.ncbi.nlm.nih.gov/pubmed/35625319
http://dx.doi.org/10.3390/antibiotics11050674
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author Becka, Scott A.
Zeiser, Elise T.
LiPuma, John J.
Papp-Wallace, Krisztina M.
author_facet Becka, Scott A.
Zeiser, Elise T.
LiPuma, John J.
Papp-Wallace, Krisztina M.
author_sort Becka, Scott A.
collection PubMed
description Tebipenem-pivoxil hydrobromide, an orally bioavailable carbapenem, is currently in clinical development for the treatment of extended-spectrum β-lactamase- and AmpC-producing Enterobacterales. Previously, tebipenem was found to possess antimicrobial activity against the biothreat pathogens, Burkholderia pseudomallei and Burkholderia mallei. Thus, herein, tebipenem was evaluated against a panel of 150 curated strains of Burkholderia cepacia complex (Bcc) and Burkholderia gladioli, pathogens that infect people who are immunocompromised or have cystic fibrosis. Using the provisional susceptibility breakpoint of 0.12 mg/L for tebipenem, 100% of the Bcc and B. gladioli tested as being provisionally resistant to tebipenem. Bcc and B. gladioli possess two inducible chromosomal β-lactamases, PenA and AmpC. Using purified PenA1 and AmpC1, model β-lactamases expressed in Burkholderia multivorans ATCC 17616, PenA1 was found to slowly hydrolyze tebipenem, while AmpC1 was inhibited by tebipenem with a k(2)/K value of 1.9 ± 0.1 × 10(3) M(−1)s(−1). In addition, tebipenem was found to be a weak inducer of bla(PenA1) expression. The combination of the slow hydrolysis by PenA1 and weak induction of bla(PenA1) likely compromises the potency of tebipenem against Bcc and B. gladioli.
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spelling pubmed-91374792022-05-28 The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States Becka, Scott A. Zeiser, Elise T. LiPuma, John J. Papp-Wallace, Krisztina M. Antibiotics (Basel) Article Tebipenem-pivoxil hydrobromide, an orally bioavailable carbapenem, is currently in clinical development for the treatment of extended-spectrum β-lactamase- and AmpC-producing Enterobacterales. Previously, tebipenem was found to possess antimicrobial activity against the biothreat pathogens, Burkholderia pseudomallei and Burkholderia mallei. Thus, herein, tebipenem was evaluated against a panel of 150 curated strains of Burkholderia cepacia complex (Bcc) and Burkholderia gladioli, pathogens that infect people who are immunocompromised or have cystic fibrosis. Using the provisional susceptibility breakpoint of 0.12 mg/L for tebipenem, 100% of the Bcc and B. gladioli tested as being provisionally resistant to tebipenem. Bcc and B. gladioli possess two inducible chromosomal β-lactamases, PenA and AmpC. Using purified PenA1 and AmpC1, model β-lactamases expressed in Burkholderia multivorans ATCC 17616, PenA1 was found to slowly hydrolyze tebipenem, while AmpC1 was inhibited by tebipenem with a k(2)/K value of 1.9 ± 0.1 × 10(3) M(−1)s(−1). In addition, tebipenem was found to be a weak inducer of bla(PenA1) expression. The combination of the slow hydrolysis by PenA1 and weak induction of bla(PenA1) likely compromises the potency of tebipenem against Bcc and B. gladioli. MDPI 2022-05-17 /pmc/articles/PMC9137479/ /pubmed/35625319 http://dx.doi.org/10.3390/antibiotics11050674 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Becka, Scott A.
Zeiser, Elise T.
LiPuma, John J.
Papp-Wallace, Krisztina M.
The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States
title The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States
title_full The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States
title_fullStr The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States
title_full_unstemmed The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States
title_short The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States
title_sort class a β-lactamase produced by burkholderia species compromises the potency of tebipenem against a panel of isolates from the united states
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137479/
https://www.ncbi.nlm.nih.gov/pubmed/35625319
http://dx.doi.org/10.3390/antibiotics11050674
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