N-Aryl Mercaptopropionamides as Broad-Spectrum Inhibitors of Metallo-ß-Lactamases.
J Med Chem
; 65(5): 3913-3922, 2022 03 10.
Article
em En
| MEDLINE
| ID: mdl-35188771
ABSTRACT
Drug-resistant pathogens pose a global challenge to public health as they cause diseases that are extremely difficult to cure. Metallo-ß-lactamases (MBLs) are a diverse set of zinc-containing enzymes that catalyze the hydrolysis of ß-lactam drugs, including carbapenems, which are considered as the last resort to fight severe infections. To restore the activity of current ß-lactam antibiotics and to offer an orthogonal strategy to the discovery of new antibiotics, we have identified a series of polar N-aryl mercaptopropionamide derivatives as potent inhibitors of several class B1 MBLs. We have identified a hit structure with high selectivity restoring the effect of imipenem and reducing minimum inhibitory concentration (MIC) values up to 256-fold in resistant isolates from Escherichia coli. Furthermore, the combination of imipenem with our inhibitor showed in vivo efficacy in a Galleria mellonella model, increasing the survival rate of infected larvae by up to 31%.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Beta-Lactamases
/
Inibidores de beta-Lactamases
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article