RESUMEN
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.
Asunto(s)
Proteínas Bacterianas , Carbapenémicos/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Hexosiltransferasas , Peptidil Transferasas , Carbapenémicos/química , Carbapenémicos/farmacología , Proteínas Portadoras/efectos de los fármacos , Proteínas Portadoras/metabolismo , Farmacorresistencia Microbiana , Pruebas de Sensibilidad Microbiana , Muramoilpentapéptido Carboxipeptidasa/efectos de los fármacos , Muramoilpentapéptido Carboxipeptidasa/metabolismo , Proteínas de Unión a las PenicilinasRESUMEN
Pharmacokinetic parameters were determined for imipenem-cilastatin and a carbapenem antibiotic, L-695,256, active against methicillin-resistant Staphylococcus aureus in rhesus monkeys and a chimpanzee. L-695,256 had larger areas under the concentration-time curve than imipenem-cilastatin (30 +/- 5 versus 24 +/- 1 micrograms.h/ml in the rhesus monkeys and 77 versus 60 micrograms.h/ml in the chimpanzee) and a longer half-life at beta phase (1.2 +/- 0.1 versus 0.6 +/- 0.1 h in the rhesus monkeys and 1.0 versus 0.8 h in the chimpanzee). Resistance to hydrolysis by the renal dehydropeptidase-I allowed L-695,256 to be administered as a single agent.
Asunto(s)
Antibacterianos/farmacocinética , Staphylococcus aureus/efectos de los fármacos , Animales , Carbapenémicos/farmacocinética , Cilastatina/farmacocinética , Combinación Cilastatina e Imipenem , Dipeptidasas/metabolismo , Combinación de Medicamentos , Quimioterapia Combinada/farmacocinética , Semivida , Imidazoles/farmacocinética , Imipenem/farmacocinética , Inyecciones Intravenosas , Riñón/enzimología , Macaca mulatta , Masculino , Resistencia a la Meticilina , Pan troglodytesRESUMEN
The labile tert-butyldimethylsilyl esters of the azetidinones 6-8b served as the crucial synthons in the preparation of the potentially useful ylide pyridyl thio esters 18-20. These intermediates were utilized to synthesize a host of title carbapenems 25-30d, 32, and 49-53. The antimicrobial properties and DHP-I susceptibility of these carbapenems were studied with reference to thienamycin.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Antibacterianos/síntesis química , Fenómenos Químicos , Química , Relación Estructura-Actividad , Tienamicinas/farmacologíaRESUMEN
Several possible strategems for overcoming the development of bacterial resistance are discussed. The design of new drugs that resist microbial inactivation is reviewed, with particular emphasis on the aminoglycoside and beta-lactam antibiotics. Examples of alteration of the inactivation site, decreased enzyme affinity, steric hindrance of enzymic inactivation, and semiempirical systematic modification of the parent antibiotic are presented. The role of the 7-alpha-methoxy group in cefoxitin and the cephamycins in conferring stability in the presence of beta-lactamase is best rationalized by its steric bulk. The effects of other 7-alpha-substituents are also discussed.
