RESUMEN
Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of ß-lactamases, enzymes that inactivate ß-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new ß-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded-spectrum serine ß-lactamase inhibitors that potently inhibit clinically relevant class A, C and D ß-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of ß-lactam activity in a broad range of MDR Gram-negative pathogens. One of the most promising combinations is sulbactam-ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Animales , Compuestos de Azabiciclo/uso terapéutico , Compuestos de Azabiciclo/toxicidad , Carbapenémicos/farmacología , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Enterobacteriaceae/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Ratones , Modelos Moleculares , Proteínas de Unión a las Penicilinas/antagonistas & inhibidores , Ratas , Sulbactam/química , Sulbactam/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Inhibidores de beta-Lactamasas/toxicidad , beta-Lactamasas/metabolismo , beta-Lactamas/farmacologíaRESUMEN
Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.
Asunto(s)
Adenosina/química , Antibacterianos/síntesis química , ADN Ligasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , NAD/química , Adenina/química , Administración Oral , Animales , Antibacterianos/química , Disponibilidad Biológica , Cromatografía Liquida/métodos , ADN Ligasas/química , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Flúor/química , Concentración 50 Inhibidora , Espectrometría de Masas/métodos , Modelos Químicos , RatasRESUMEN
Optimization of adenosine analog inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. Antibacterial activity against Streptococcus pneumoniae and Staphylococcus aureus was improved by modification of the 2-position substituent on the adenine ring and 3'- and 5'-substituents on the ribose. Compounds with logD values 1.5-2.5 maximized potency and maintained drug-like physical properties.