RESUMO
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.
Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Animais , Compostos Azabicíclicos/uso terapêutico , Compostos Azabicíclicos/toxicidade , Carbapenêmicos/farmacologia , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Camundongos , Modelos Moleculares , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Ratos , Sulbactam/química , Sulbactam/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Inibidores de beta-Lactamases/toxicidade , beta-Lactamases/metabolismo , beta-Lactamas/farmacologiaRESUMO
INTRODUCTION: Preclinical assessment of the heart rate corrected QT interval (QTc) is an important component of the cardiovascular safety evaluation in drug discovery. Here we aimed to quantify the translational relationship between QTc prolongation and shortening in the conscious telemetered dog and humans by a retrospective pharmacokinetic-pharmacodynamic (PKPD) analysis. METHODS: QTc effects of 2 proprietary compounds and 2 reference drugs (moxifloxacin and dofetilide) were quantified in conscious dogs and healthy volunteers via a linear and Emax pharmacokinetic-pharmacodynamic models. The translational relationship was quantified by correlating the QTc response from dog and human at matching free drug concentrations. RESULTS: A consistent translational relationship was found at low delta-QTc intervals indicating that a QTc change of 2.5-8 ms in dog would correspond to a 10 ms change in human. DISCUSSION: The translational relationship developed here can be used to predict the QTc liability in human using preclinical dog data. It could therefore help protect the health of human volunteers, for example by appropriate clinical study design and dose selection, as well as improve future decision-making and help reduce compound attrition due to changes in QT interval.