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Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze...

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Autores principales: Palacios, Antonela R., Rossi, María-Agustina, Mahler, Graciela S., Vila, Alejandro J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356002/
https://www.ncbi.nlm.nih.gov/pubmed/32503337
http://dx.doi.org/10.3390/biom10060854
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author Palacios, Antonela R.
Rossi, María-Agustina
Mahler, Graciela S.
Vila, Alejandro J.
author_facet Palacios, Antonela R.
Rossi, María-Agustina
Mahler, Graciela S.
Vila, Alejandro J.
author_sort Palacios, Antonela R.
collection PubMed
description β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.
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spelling pubmed-73560022020-07-22 Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism Palacios, Antonela R. Rossi, María-Agustina Mahler, Graciela S. Vila, Alejandro J. Biomolecules Review β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis. MDPI 2020-06-03 /pmc/articles/PMC7356002/ /pubmed/32503337 http://dx.doi.org/10.3390/biom10060854 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 Review
Palacios, Antonela R.
Rossi, María-Agustina
Mahler, Graciela S.
Vila, Alejandro J.
Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism
title Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism
title_full Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism
title_fullStr Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism
title_full_unstemmed Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism
title_short Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism
title_sort metallo-β-lactamase inhibitors inspired on snapshots from the catalytic mechanism
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356002/
https://www.ncbi.nlm.nih.gov/pubmed/32503337
http://dx.doi.org/10.3390/biom10060854
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