Studies on the inhibition of AmpC and other ß-lactamases by cyclic boronates.
Biochim Biophys Acta Gen Subj
; 1863(4): 742-748, 2019 04.
Article
em En
| MEDLINE
| ID: mdl-30738906
ABSTRACT
BACKGROUND:
The ß-lactam antibiotics represent the most successful drug class for treatment of bacterial infections. Resistance to them, importantly via production of ß-lactamases, which collectively are able to hydrolyse all classes of ß-lactams, threatens their continued widespread use. Bicyclic boronates show potential as broad spectrum inhibitors of the mechanistically distinct serine- (SBL) and metallo- (MBL) ß-lactamase families.METHODS:
Using biophysical methods, including crystallographic analysis, we have investigated the binding mode of bicyclic boronates to clinically important ß-lactamases. Induction experiments and agar-based MIC screening against MDR-Enterobacteriaceae (nâ¯=â¯132) were used to evaluate induction properties and the in vitro efficacy of a bicyclic boronate in combination with meropenem.RESULTS:
Crystallographic analysis of a bicyclic boronate in complex with AmpC from Pseudomonas aeruginosa reveals it binds to form a tetrahedral boronate species. Microbiological studies on the clinical coverage (in combination with meropenem) and induction of ß-lactamases by bicyclic boronates further support the promise of such compounds as broad spectrum ß-lactamase inhibitors.CONCLUSIONS:
Together with reported studies on the structural basis of their inhibition of class A, B and D ß-lactamases, biophysical studies, including crystallographic analysis, support the proposal that bicyclic boronates mimic tetrahedral intermediates common to SBL and MBL catalysis. GENERALSIGNIFICANCE:
Bicyclic boronates are a new generation of broad spectrum inhibitors of both SBLs and MBLs.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Beta-Lactamases
/
Ácidos Borônicos
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Inibidores de beta-Lactamases
/
Antibacterianos
Idioma:
En
Revista:
Biochim Biophys Acta Gen Subj
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido