RESUMO
Spiropiperidine naphthyridinone inhibitors of Staphylococcus aureus and Escherichia coli FabI have been prepared. Compounds 14a and 14c were identified as having sub-nanomolar E. coli FabI activity and are among the most potent FabI inhibitors yet described. The structural model of 14a bound to E. coli FabI is shown.
Assuntos
Antibacterianos/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Escherichia coli/enzimologia , Naftiridinas/farmacologia , Piperidinas/farmacologia , Compostos de Espiro/farmacologia , Staphylococcus aureus/enzimologia , Antibacterianos/química , Domínio Catalítico , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/química , Modelos Moleculares , Naftiridinas/química , Piperidinas/química , Ligação Proteica , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
In this article, we describe for the first time the high-resolution crystal structure of a phenylalanine tRNA synthetase from the pathogenic bacterium Staphylococcus haemolyticus. We demonstrate the subtle yet important structural differences between this enzyme and the previously described Thermus thermophilus ortholog. We also explain the structure-activity relationship of several recently reported inhibitors. The native enzyme crystals were of poor quality--they only diffracted X-rays to 3-5A resolution. Therefore, we have executed a rational surface mutagenesis strategy that has yielded crystals of this 2300-amino acid multidomain protein, diffracting to 2A or better. This methodology is discussed and contrasted with the more traditional domain truncation approach.
