RESUMO
The diaminopimelic acid (DAP) analog, 3-chloro-DAP, was synthesized and tested as the racemic acid for antibacterial activity and for inhibition of DAP epimerase. 3-Chloro-DAP was a potent inhibitor of DAP epimerase purified from Escherichia coli (Ki = 200 nM), and it is argued that 3-chloro-DAP is converted to a tight-binding transition state analog at the active site of this enzyme. Furthermore, 3-chloro-DAP inhibited growth of two E. coli mutants. In one of the mutants known for supersusceptibility to beta-lactams, inhibition was not seen until the mid-log phase of growth, while in the other mutant, a DAP auxotroph, inhibition occurred much earlier. Growth inhibition was reversed by DAP in both strains. In the auxotroph, the reversal was specific for meso-DAP, indicating that DAP epimerase was the target for 3-chloro-DAP. Thus we suggest a novel mechanism of bacterial growth inhibition which depends on DAP epimerase inhibition by a DAP analog.
Assuntos
Isomerases de Aminoácido , Diamino Aminoácidos/farmacologia , Ácido Diaminopimélico/farmacologia , Escherichia coli/efeitos dos fármacos , Isomerases/antagonistas & inibidores , Racemases e Epimerases/antagonistas & inibidores , Fenômenos Químicos , Química , Ácido Diaminopimélico/análogos & derivados , Ácido Diaminopimélico/síntese química , Escherichia coli/enzimologia , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , MutaçãoRESUMO
Three cephalosporin derivatives were prepared from 1,4-dihydro-4-oxypyridine-1-acetic acid. These were the 7-aminocephalosporanic acid (7-ACA) derivative and the compounds with 5-methyl-1,3,4-thiadiazol-2-thiol and 1-methyl-1,2,3,4-tetrazole-5-thiol at C-3 of the cephalosporin nucleus. The antibacterial activity of the 7-ACA derivative was comparable to cephalothin, and that of the other two derivatives was comparable to cefazolin. The 7-ACA derivative, compared to cephalothin, was significantly less metabolized, was less protein bound, and had a longer half life.
Assuntos
Cefalosporinas/síntese química , Animais , Bactérias/efeitos dos fármacos , Bioensaio , Proteínas Sanguíneas/metabolismo , Cefalosporinas/metabolismo , Cefalosporinas/farmacologia , Resistência Microbiana a Medicamentos , Masculino , Camundongos , Ligação ProteicaRESUMO
A number of orally active cephalosporins and penicillins with interesting biological activity were synthesized. Two of these, 7-[[[3,4-(methylenedioxy)phenyl]glycyl]amino]deacetoxycephalosporanic acid and 7-[[2-(2,3-dihydro-5-benzofuranyl)glycyl]amino]deacetoxycephalosporanic acid were considerably more active than cephalexin both in vitro and in vivo against staphylococcal and streptococcal infections.
Assuntos
Cefalosporinas/síntese química , Penicilinas/síntese química , Administração Oral , Animais , Infecções Bacterianas/tratamento farmacológico , Cefalosporinas/administração & dosagem , Cefalosporinas/metabolismo , Cefalosporinas/farmacologia , Injeções Subcutâneas , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Penicilinas/administração & dosagem , Penicilinas/metabolismo , Penicilinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of 1-pyrrole- and 1-indoleacetamido derivatives of 3-heteroaryl-substituted cephalosporins was prepared. The most active compound in the series was 7-[[2-(1-pyrryl)acetyl]amino]-3-[[(1-methyltetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (6), which showed comparable potency in vitro and in vivo to that of cefazolin, and, in addition, was more potent than cefazolin against Enterobacter sp. and Providencia stuartii.