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

Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Ocampo and Esmeralda, S2002LRK Rosario, Argentina
Laboratorio de Química Farmacéutica, Facultad de Química, Universidad de la Republica (UdelaR), Montevideo 11800, Uruguay
Área Biofísica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, S2002LRK Rosario, Argentina
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomolecules 2020, 10(6), 854;
Received: 8 May 2020 / Revised: 31 May 2020 / Accepted: 1 June 2020 / Published: 3 June 2020
(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)
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. View Full-Text
Keywords: metallo-β-lactamases; mechanism-based inhibitors; antibiotic resistance; reaction mechanism metallo-β-lactamases; mechanism-based inhibitors; antibiotic resistance; reaction mechanism
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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.

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