RESUMO
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.
Assuntos
Proteínas de Bactérias , Carbapenêmicos/imunologia , Carbapenêmicos/farmacologia , Desenho de Fármacos , Hexosiltransferases , Lactamas/farmacologia , Peptidil Transferases , Tiazóis/farmacologia , Animais , Anticorpos/sangue , Carbapenêmicos/química , Carbapenêmicos/metabolismo , Carbapenêmicos/toxicidade , Proteínas de Transporte/metabolismo , Dipeptidases/metabolismo , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Enterococcus/efeitos dos fármacos , Eritrócitos/imunologia , Haptenos , Humanos , Epitopos Imunodominantes , Imunoglobulina G/sangue , Lactamas/síntese química , Lactamas/química , Lactamas/metabolismo , Ativação Linfocitária , Macaca mulatta , Camundongos , Camundongos Endogâmicos DBA , Testes de Sensibilidade Microbiana , Muramilpentapeptídeo Carboxipeptidase/metabolismo , Proteínas de Ligação às Penicilinas , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/química , Tiazóis/metabolismoRESUMO
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.
Assuntos
Carbapenêmicos/farmacologia , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Resistência às Cefalosporinas , Escherichia coli/enzimologia , Klebsiella pneumoniae/enzimologia , Testes de Sensibilidade Microbiana , beta-Lactamases/metabolismoRESUMO
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.
Assuntos
Proteínas de Bactérias , Carbapenêmicos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Hexosiltransferases , Peptidil Transferases , Carbapenêmicos/química , Carbapenêmicos/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Resistência Microbiana a Medicamentos , Testes de Sensibilidade Microbiana , Muramilpentapeptídeo Carboxipeptidase/efeitos dos fármacos , Muramilpentapeptídeo Carboxipeptidase/metabolismo , Proteínas de Ligação às PenicilinasRESUMO
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.