Metallo-β-lactamase inhibitors inspired on snapshots from the catalytic mechanism
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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.
Para citar este articulo: Palacios, A.R.; Rossi, M.-A.; Mahler, G.S.; Vila, A.J. Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism. Biomolecules 2020, 10, 854. https://doi.org/10.3390/biom10060854
Para citar este articulo: Palacios, A.R.; Rossi, M.-A.; Mahler, G.S.; Vila, A.J. Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism. Biomolecules 2020, 10, 854. https://doi.org/10.3390/biom10060854
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