RESUMEN
A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.
Asunto(s)
Amidas/síntesis química , Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Prolina/análogos & derivados , Prolina/síntesis química , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Administración Oral , Amidas/farmacología , Amidohidrolasas/metabolismo , Animales , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/crecimiento & desarrollo , Humanos , Inyecciones Intravenosas , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Prolina/farmacología , Ratas , Infecciones del Sistema Respiratorio/microbiología , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
The synthesis and antibacterial activity of 3-methylenepyrrolidine formyl hydroxyamino derivatives are reported. The antibacterial activities of these derivatives were evaluated to discover SAR at P(1') and P(3') positions, and most of these derivatives exhibit better in vitro antibacterial activity than existing drugs against drug-resistant clinical isolates including MRSA, PRSP, and Haemophilus influenzae.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Inhibidores Enzimáticos/síntesis química , Pirrolidinas/química , Amidohidrolasas/metabolismo , Antibacterianos/química , Antibacterianos/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Haemophilus influenzae/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Pirrolidinas/síntesis química , Pirrolidinas/farmacologíaRESUMEN
The in vitro activity of retapamulin was determined and compared to that of topical and community antibiotics. The MIC(90)s of retapamulin against Staphylococcus aureus and Streptococcus pyogenes were 0.12 microg/ml and 0.016 microg/ml, respectively. Retapamulin has a low propensity to select resistance and produces an in vitro postantibiotic effect.