RESUMO
Resistance to antibiotics is currently a major health concern in treating infectious diseases. The most common mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamases, which destroy beta-lactam antibiotics before they reach the bacterial target. Combination therapy, which involves treatment with a beta-lactam antibiotic and a beta-lactamase inhibitor, has been successfully used to control resistance during last two decades. Due to the lack of effectiveness of the currently available beta-lactamase inhibitors against class C enzymes and new variants of beta-lactamases, there is a need to develop an inhibitor with broad-spectrum activity. Since the discovery of clavulanic acid, there has been an enormous research effort in this area to identify better antibiotic/inhibitor combinations and to understand the molecular bases for interactions between beta-lactam antibiotics, beta-lactamases, and beta-lactamase inhibitors. This review describes some of the structure- and mechanism-based approaches to design of new beta-lactamase inhibitors and the study of probable mechanisms of inhibition using X-ray, electrospray ionization mass spectrometry, and molecular modeling techniques.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Resistência beta-Lactâmica , Inibidores de beta-Lactamases , Antibacterianos/síntese química , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Cefalosporinas/química , Cefalosporinas/farmacologia , Ácidos Clavulânicos/química , Ácidos Clavulânicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Monobactamas/química , Monobactamas/farmacologia , Ácido Penicilânico/química , Ácido Penicilânico/farmacologia , Relação Estrutura-Atividade , beta-Lactamases/classificaçãoRESUMO
Class A-class C mechanism-based beta-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with piperacillin against class A and class C producing organisms showed improvement over clinically used tazobactam.
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias , Ciclopropanos/síntese química , Compostos de Diazônio/química , Inibidores Enzimáticos/síntese química , Ródio , Serina/química , Compostos de Espiro/síntese química , Sulbactam/química , Inibidores de beta-Lactamases , beta-Lactamas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Catálise , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Pseudomonas aeruginosa/efeitos dos fármacos , Serratia marcescens/efeitos dos fármacos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Sulbactam/análogos & derivados , beta-Lactamases/química , beta-Lactamas/química , beta-Lactamas/farmacologiaRESUMO
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.