Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-β-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies.

Targeting Class A and C Serine β-Lactamases with a Broad-Spectrum Boronic Acid Derivative / Tondi, Donatella; Venturelli, Alberto; Bonnet, Richard; Pozzi, Cecilia; Shoichet, Brian K.; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 57(2014), pp. 5449-5458. [10.1021/jm5006572]

Targeting Class A and C Serine β-Lactamases with a Broad-Spectrum Boronic Acid Derivative

Donatella Tondi;Alberto Venturelli;Maria Paola Costi
2014

Abstract

Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-β-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies.
28-apr-2014
57
5449
5458
Targeting Class A and C Serine β-Lactamases with a Broad-Spectrum Boronic Acid Derivative / Tondi, Donatella; Venturelli, Alberto; Bonnet, Richard; Pozzi, Cecilia; Shoichet, Brian K.; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 57(2014), pp. 5449-5458. [10.1021/jm5006572]
Tondi, Donatella; Venturelli, Alberto; Bonnet, Richard; Pozzi, Cecilia; Shoichet, Brian K.; Costi, Maria Paola
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1058115
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