RESUMEN
A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.
Asunto(s)
Proteínas Bacterianas , Carbapenémicos/inmunología , Carbapenémicos/farmacología , Diseño de Fármacos , Hexosiltransferasas , Lactamas/farmacología , Peptidil Transferasas , Tiazoles/farmacología , Animales , Anticuerpos/sangre , Carbapenémicos/química , Carbapenémicos/metabolismo , Carbapenémicos/toxicidad , Proteínas Portadoras/metabolismo , Dipeptidasas/metabolismo , Farmacorresistencia Microbiana , Resistencia a Múltiples Medicamentos , Enterococcus/efectos de los fármacos , Eritrocitos/inmunología , Haptenos , Humanos , Epítopos Inmunodominantes , Inmunoglobulina G/sangre , Lactamas/síntesis química , Lactamas/química , Lactamas/metabolismo , Activación de Linfocitos , Macaca mulatta , Ratones , Ratones Endogámicos DBA , Pruebas de Sensibilidad Microbiana , Muramoilpentapéptido Carboxipeptidasa/metabolismo , Proteínas de Unión a las Penicilinas , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus/efectos de los fármacos , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/metabolismoRESUMEN
A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.