RESUMEN
An important mechanism of bacterial resistance to beta-lactam antibiotics is inactivation by beta-lactam-hydrolyzing enzymes (beta-lactamases). The evolution of the extended-spectrum beta-lactamases (ESBLs) is associated with extensive use of beta-lactam antibiotics, particularly cephalosporins, and is a serious threat to therapeutic efficacy. ESBLs and broad-spectrum beta-lactamases (BDSBLs) are plasmid-mediated class A enzymes produced by gram-negative pathogens, principally Escherichia coli and Klebsiella pneumoniae. MK-0826 was highly potent against all ESBL- and BDSBL-producing K. pneumoniae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 microgram/ml). In E. coli, this activity was associated with high-affinity binding to penicillin-binding proteins 2 and 3. When the inoculum level was increased 10-fold, increasing the amount of beta-lactamase present, the MK-0826 MIC range increased to 0.008 to 1 microgram/ml. By comparison, similar observations were made with meropenem while imipenem MICs were usually less affected. Not surprisingly, MIC increases with noncarbapenem beta-lactams were generally substantially greater, resulting in resistance in many cases. E. coli strains that produce chromosomal (Bush group 1) beta-lactamase served as controls. All three carbapenems were subject to an inoculum effect with the majority of the BDSBL- and ESBL-producers but not the Bush group 1 strains, implying some effect of the plasmid-borne enzymes on potency. Importantly, MK-0826 MICs remained at or below 1 microgram/ml under all test conditions.
Asunto(s)
Carbapenémicos/farmacología , Escherichia coli/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Resistencia a las Cefalosporinas , Escherichia coli/enzimología , Klebsiella pneumoniae/enzimología , Pruebas de Sensibilidad Microbiana , beta-Lactamasas/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.
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
A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.