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Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors

Boronic acid transition-state analog inhibitors (BATSIs) are partners with β-lactam antibiotics for the treatment of complex bacterial infections. Herein, microbiological, biochemical, and structural findings on four BATSIs with the FOX-4 cephamycinase, a class C β-lactamase that rapidly hydrolyzes...

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Autores principales: Lefurgy, Scott T., Caselli, Emilia, Taracila, Magdalena A., Malashkevich, Vladimir N., Biju, Beena, Papp-Wallace, Krisztina M., Bonanno, Jeffrey B., Prati, Fabio, Almo, Steven C., Bonomo, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277225/
https://www.ncbi.nlm.nih.gov/pubmed/32349291
http://dx.doi.org/10.3390/biom10050671
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author Lefurgy, Scott T.
Caselli, Emilia
Taracila, Magdalena A.
Malashkevich, Vladimir N.
Biju, Beena
Papp-Wallace, Krisztina M.
Bonanno, Jeffrey B.
Prati, Fabio
Almo, Steven C.
Bonomo, Robert A.
author_facet Lefurgy, Scott T.
Caselli, Emilia
Taracila, Magdalena A.
Malashkevich, Vladimir N.
Biju, Beena
Papp-Wallace, Krisztina M.
Bonanno, Jeffrey B.
Prati, Fabio
Almo, Steven C.
Bonomo, Robert A.
author_sort Lefurgy, Scott T.
collection PubMed
description Boronic acid transition-state analog inhibitors (BATSIs) are partners with β-lactam antibiotics for the treatment of complex bacterial infections. Herein, microbiological, biochemical, and structural findings on four BATSIs with the FOX-4 cephamycinase, a class C β-lactamase that rapidly hydrolyzes cefoxitin, are revealed. FOX-4 is an extended-spectrum class C cephalosporinase that demonstrates conformational flexibility when complexed with certain ligands. Like other β-lactamases of this class, studies on FOX-4 reveal important insights into structure–activity relationships. We show that SM23, a BATSI, shows both remarkable flexibility and affinity, binding similarly to other β-lactamases, yet retaining an IC(50) value < 0.1 μM. Our analyses open up new opportunities for the design of novel transition-state analogs of class C enzymes.
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spelling pubmed-72772252020-06-15 Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors Lefurgy, Scott T. Caselli, Emilia Taracila, Magdalena A. Malashkevich, Vladimir N. Biju, Beena Papp-Wallace, Krisztina M. Bonanno, Jeffrey B. Prati, Fabio Almo, Steven C. Bonomo, Robert A. Biomolecules Article Boronic acid transition-state analog inhibitors (BATSIs) are partners with β-lactam antibiotics for the treatment of complex bacterial infections. Herein, microbiological, biochemical, and structural findings on four BATSIs with the FOX-4 cephamycinase, a class C β-lactamase that rapidly hydrolyzes cefoxitin, are revealed. FOX-4 is an extended-spectrum class C cephalosporinase that demonstrates conformational flexibility when complexed with certain ligands. Like other β-lactamases of this class, studies on FOX-4 reveal important insights into structure–activity relationships. We show that SM23, a BATSI, shows both remarkable flexibility and affinity, binding similarly to other β-lactamases, yet retaining an IC(50) value < 0.1 μM. Our analyses open up new opportunities for the design of novel transition-state analogs of class C enzymes. MDPI 2020-04-27 /pmc/articles/PMC7277225/ /pubmed/32349291 http://dx.doi.org/10.3390/biom10050671 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lefurgy, Scott T.
Caselli, Emilia
Taracila, Magdalena A.
Malashkevich, Vladimir N.
Biju, Beena
Papp-Wallace, Krisztina M.
Bonanno, Jeffrey B.
Prati, Fabio
Almo, Steven C.
Bonomo, Robert A.
Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors
title Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors
title_full Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors
title_fullStr Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors
title_full_unstemmed Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors
title_short Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors
title_sort structures of fox-4 cephamycinase in complex with transition-state analog inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277225/
https://www.ncbi.nlm.nih.gov/pubmed/32349291
http://dx.doi.org/10.3390/biom10050671
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