Microbial infections represent a major risk to human health. In this respect, β-lactam antibiotics constitute a key therapeutic resource against such infections. However, we are facing increasing microbial resistance to antibiotic treatment and particularly worrisome is the emergence of resistant bacterial strains towards β-lactam antibiotics that can rapidly disseminate worldwide. β-lactamase enzymes are the main determinant of bacterial resistance and among them metallo-β-lactamases (MBLs) are most threatening, as exemplified by the recent resistance outbreaks due to New Delhi β-lactamase 1 (NDM-1) producing bacteria. MBLs are mono or di-zinc enzymes able to inactivate clinically important β-lactam antibiotics including carbapenems, which are used as a last resort therapy in severe infections. Under this scenery, the discovery of new potent inhibitors of MBLs becomes an urgent need and X-ray crystallography of MBLs in complex with small molecule inhibitors provides the possibility to accelerate the process of drug discovery. We present here the atomic-resolution crystal structures of BJP-1, a di-zinc MBL, in complex with two small molecules and their comparison with other MBL complexes with inhibitors. These structural data, besides providing hints about the mechanism of di-zinc MBLs, might be the starting point for a fragment-based lead-discovery program.

Di Pisa, F., Pozzi, C., Benvenuti, M., Docquier, J., De Luca, F., Mangani, S. (2018). Boric acid and acetate anion binding to subclass B3 metallo-β-lactamase BJP-1 provides clues for mechanism of action and inhibitor design. INORGANICA CHIMICA ACTA, 470, 331-341 [10.1016/j.ica.2017.07.030].

Boric acid and acetate anion binding to subclass B3 metallo-β-lactamase BJP-1 provides clues for mechanism of action and inhibitor design

Di Pisa, Flavio
Investigation
;
Pozzi, Cecilia
Investigation
;
Benvenuti, Manuela
Resources
;
Docquier, Jean-Denis
Writing – Original Draft Preparation
;
De Luca, Filomena
Investigation
;
Mangani, Stefano
Writing – Original Draft Preparation
2018-01-01

Abstract

Microbial infections represent a major risk to human health. In this respect, β-lactam antibiotics constitute a key therapeutic resource against such infections. However, we are facing increasing microbial resistance to antibiotic treatment and particularly worrisome is the emergence of resistant bacterial strains towards β-lactam antibiotics that can rapidly disseminate worldwide. β-lactamase enzymes are the main determinant of bacterial resistance and among them metallo-β-lactamases (MBLs) are most threatening, as exemplified by the recent resistance outbreaks due to New Delhi β-lactamase 1 (NDM-1) producing bacteria. MBLs are mono or di-zinc enzymes able to inactivate clinically important β-lactam antibiotics including carbapenems, which are used as a last resort therapy in severe infections. Under this scenery, the discovery of new potent inhibitors of MBLs becomes an urgent need and X-ray crystallography of MBLs in complex with small molecule inhibitors provides the possibility to accelerate the process of drug discovery. We present here the atomic-resolution crystal structures of BJP-1, a di-zinc MBL, in complex with two small molecules and their comparison with other MBL complexes with inhibitors. These structural data, besides providing hints about the mechanism of di-zinc MBLs, might be the starting point for a fragment-based lead-discovery program.
Di Pisa, F., Pozzi, C., Benvenuti, M., Docquier, J., De Luca, F., Mangani, S. (2018). Boric acid and acetate anion binding to subclass B3 metallo-β-lactamase BJP-1 provides clues for mechanism of action and inhibitor design. INORGANICA CHIMICA ACTA, 470, 331-341 [10.1016/j.ica.2017.07.030].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1033691