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Insights Into the Inhibition of MOX-1 β-Lactamase by S02030, a Boronic Acid Transition State Inhibitor
The rise of multidrug resistant (MDR) Gram-negative bacteria has accelerated the development of novel inhibitors of class A and C β-lactamases. Presently, the search for novel compounds with new mechanisms of action is a clinical and scientific priority. To this end, we determined the 2.13-Å resolut...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713471/ https://www.ncbi.nlm.nih.gov/pubmed/34970229 http://dx.doi.org/10.3389/fmicb.2021.720036 |
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author | Ishikawa, Tatsuya Furukawa, Nayuta Caselli, Emilia Prati, Fabio Taracila, Magdalena A. Bethel, Christopher R. Ishii, Yoshikazu Shimizu-Ibuka, Akiko Bonomo, Robert A. |
author_facet | Ishikawa, Tatsuya Furukawa, Nayuta Caselli, Emilia Prati, Fabio Taracila, Magdalena A. Bethel, Christopher R. Ishii, Yoshikazu Shimizu-Ibuka, Akiko Bonomo, Robert A. |
author_sort | Ishikawa, Tatsuya |
collection | PubMed |
description | The rise of multidrug resistant (MDR) Gram-negative bacteria has accelerated the development of novel inhibitors of class A and C β-lactamases. Presently, the search for novel compounds with new mechanisms of action is a clinical and scientific priority. To this end, we determined the 2.13-Å resolution crystal structure of S02030, a boronic acid transition state inhibitor (BATSI), bound to MOX-1 β-lactamase, a plasmid-borne, expanded-spectrum AmpC β-lactamase (ESAC) and compared this to the previously reported aztreonam (ATM)-bound MOX-1 structure. Superposition of these two complexes shows that S02030 binds in the active-site cavity more deeply than ATM. In contrast, the SO(3) interactions and the positional change of the β-strand amino acids from Lys315 to Asn320 were more prominent in the ATM-bound structure. MICs were performed using a fixed concentration of S02030 (4 μg/ml) as a proof of principle. Microbiological evaluation against a laboratory strain of Escherichia coli expressing MOX-1 revealed that MICs against ceftazidime are reduced from 2.0 to 0.12 μg/ml when S02030 is added at a concentration of 4 μg/ml. The IC(50) and K(i) of S02030 vs. MOX-1 were 1.25 ± 0.34 and 0.56 ± 0.03 μM, respectively. Monobactams such as ATM can serve as informative templates for design of mechanism-based inhibitors such as S02030 against ESAC β-lactamases. |
format | Online Article Text |
id | pubmed-8713471 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-87134712021-12-29 Insights Into the Inhibition of MOX-1 β-Lactamase by S02030, a Boronic Acid Transition State Inhibitor Ishikawa, Tatsuya Furukawa, Nayuta Caselli, Emilia Prati, Fabio Taracila, Magdalena A. Bethel, Christopher R. Ishii, Yoshikazu Shimizu-Ibuka, Akiko Bonomo, Robert A. Front Microbiol Microbiology The rise of multidrug resistant (MDR) Gram-negative bacteria has accelerated the development of novel inhibitors of class A and C β-lactamases. Presently, the search for novel compounds with new mechanisms of action is a clinical and scientific priority. To this end, we determined the 2.13-Å resolution crystal structure of S02030, a boronic acid transition state inhibitor (BATSI), bound to MOX-1 β-lactamase, a plasmid-borne, expanded-spectrum AmpC β-lactamase (ESAC) and compared this to the previously reported aztreonam (ATM)-bound MOX-1 structure. Superposition of these two complexes shows that S02030 binds in the active-site cavity more deeply than ATM. In contrast, the SO(3) interactions and the positional change of the β-strand amino acids from Lys315 to Asn320 were more prominent in the ATM-bound structure. MICs were performed using a fixed concentration of S02030 (4 μg/ml) as a proof of principle. Microbiological evaluation against a laboratory strain of Escherichia coli expressing MOX-1 revealed that MICs against ceftazidime are reduced from 2.0 to 0.12 μg/ml when S02030 is added at a concentration of 4 μg/ml. The IC(50) and K(i) of S02030 vs. MOX-1 were 1.25 ± 0.34 and 0.56 ± 0.03 μM, respectively. Monobactams such as ATM can serve as informative templates for design of mechanism-based inhibitors such as S02030 against ESAC β-lactamases. Frontiers Media S.A. 2021-12-14 /pmc/articles/PMC8713471/ /pubmed/34970229 http://dx.doi.org/10.3389/fmicb.2021.720036 Text en Copyright © 2021 Ishikawa, Furukawa, Caselli, Prati, Taracila, Bethel, Ishii, Shimizu-Ibuka and Bonomo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Ishikawa, Tatsuya Furukawa, Nayuta Caselli, Emilia Prati, Fabio Taracila, Magdalena A. Bethel, Christopher R. Ishii, Yoshikazu Shimizu-Ibuka, Akiko Bonomo, Robert A. Insights Into the Inhibition of MOX-1 β-Lactamase by S02030, a Boronic Acid Transition State Inhibitor |
title | Insights Into the Inhibition of MOX-1 β-Lactamase by S02030, a Boronic Acid Transition State Inhibitor |
title_full | Insights Into the Inhibition of MOX-1 β-Lactamase by S02030, a Boronic Acid Transition State Inhibitor |
title_fullStr | Insights Into the Inhibition of MOX-1 β-Lactamase by S02030, a Boronic Acid Transition State Inhibitor |
title_full_unstemmed | Insights Into the Inhibition of MOX-1 β-Lactamase by S02030, a Boronic Acid Transition State Inhibitor |
title_short | Insights Into the Inhibition of MOX-1 β-Lactamase by S02030, a Boronic Acid Transition State Inhibitor |
title_sort | insights into the inhibition of mox-1 β-lactamase by s02030, a boronic acid transition state inhibitor |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713471/ https://www.ncbi.nlm.nih.gov/pubmed/34970229 http://dx.doi.org/10.3389/fmicb.2021.720036 |
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