RESUMO
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.
Assuntos
Acinetobacter/efeitos dos fármacos , Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Octanos/química , beta-Lactamases/química , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Sítios de Ligação , Carbapenêmicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Octanos/metabolismo , Octanos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/metabolismo , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismoRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Infecções por Enterobacteriaceae/tratamento farmacológico , Inibidores de beta-Lactamases/química , Carbapenêmicos/farmacologia , Cristalografia por Raios X , Concentração Inibidora 50 , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/farmacologia , beta-LactamasesRESUMO
During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.