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 the important ß-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-ß-lactamase (MBL) enzymes. To address this resistance issue, multiple ß-lactam/ß-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.