RESUMEN
The diazabicyclooctanes (DBOs) are a class of serine ß-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of ß-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of ß-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO "critical priority pathogen" producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure-activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.
Asunto(s)
Acinetobacter/efectos de los fármacos , Antibacterianos/farmacología , Enterobacteriaceae/efectos de los fármacos , Octanos/química , beta-Lactamasas/química , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Sitios de Unión , Carbapenémicos/farmacología , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana/efectos de los fármacos , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Octanos/metabolismo , Octanos/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/metabolismo , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismoRESUMEN
The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-ß-lactamase (MBL) and serine-ß-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new ß-lactamase inhibitors to be used in conjunction with carbapenems and other ß-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-ß-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.