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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7277225 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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