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An Elusive Task: A Clinically Useful Inhibitor of Metallo-β-Lactamases

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Zinc Enzyme Inhibitors

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 22))

Abstract

Multidrug-resistant bacterial infections have become in recent years an increasingly worrisome problem in the medical community. The β-lactams are the most used antibiotics consisting in more than 60% of the prescribed antibacterials. Indeed, carbapenems are considered as “last resort” antibiotics for the treatment of several pathogens that are difficult to eradicate. The most widespread bacterial resistant mechanism against β-lactams consists in the expression of β-lactamases which inactivate these compounds by hydrolyzing the β-lactam bond. Metallo-β-lactamases (MBLs) are metal-dependent enzymes that are able to coordinate one or two Zn(II) ions in their active site which are essential for the catalytic mechanism. In view of this scenario, the search and identification of inhibitors against these enzymes is of outmost importance for the rescue of the antibiotic activity of the β-lactams. Here we present a critical analysis of the different chemical motifs that had been reported as MBL inhibitors, inspected within the context of mechanistic and structural information with the goal of identifying common aspects that can be used for the development of more efficient and broad-spectrum leads. We also suggest possible future directions for the development of this exciting research field.

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Acknowledgements

The work in Rosario has been supported by grants from NIH (1R01AI100560) and ANCPyT. MMG is recipient of a PhD fellowship from CONICET, and AJV is a Staff member from CONICET.

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  1. Facultad de Ciencias Bioquímicas y Farmacéuticas, IBR (Instituto de Biología Molecular y Celular de Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Rosario, 2000, Rosario, Argentina

    Mariano M. González & Alejandro J. Vila

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  1. Mariano M. González
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  2. Alejandro J. Vila
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Correspondence to Alejandro J. Vila .

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  1. Neurofarba Department, University of Florence, Sesto Fiorentino (Firenze), Italy

    Claudiu T. Supuran

  2. Neurofarba Department, University of Florence, Sesto Fiorentino (Firenze), Italy

    Clemente Capasso

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González, M.M., Vila, A.J. (2016). An Elusive Task: A Clinically Useful Inhibitor of Metallo-β-Lactamases. In: Supuran, C., Capasso, C. (eds) Zinc Enzyme Inhibitors. Topics in Medicinal Chemistry, vol 22. Springer, Cham. https://doi.org/10.1007/7355_2016_6

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