RESUMO
Due to the persistence and spread of antibiotic resistance, the discovery and exploitation of new antibiotic targets should be the subject of intensive research. Effective strategies are required to develop antibiotic alternatives. Antibiotics that act on new targets or via novel mechanisms have the greatest likelihood of overcoming resistance. In particular, there is a lack of specific antibiotics for Pseudomonas aeruginosa, one of the leading causes of healthcare-associated infections, exhibiting high resistance levels. Herein we describe how structure-based drug design can be used to achieve new antibiotics for the treatment of Pseudomonas aeruginosa infection, using an essential enzyme of the fatty acid synthesis pathway from P. aeruginosa as an example.
Assuntos
Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Descoberta de Drogas , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Antibacterianos/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Descoberta de Drogas/métodos , Farmacorresistência Bacteriana , Humanos , Incidência , Mutação , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Relação Estrutura-AtividadeRESUMO
Fatty acid biosynthesis is an essential component of metabolism in both eukaryotes and prokaryotes. The fatty acid biosynthetic pathway of Gram-negative bacteria is an established therapeutic target. Two homologous enzymes FabA and FabZ catalyze a key step in fatty acid biosynthesis; both dehydrate hydroxyacyl fatty acids that are coupled via a phosphopantetheine to an acyl carrier protein (ACP). The resulting trans-2-enoyl-ACP is further polymerized in a processive manner. FabA, however, carries out a second reaction involving isomerization of trans-2-enoyl fatty acid to cis-3-enoyl fatty acid. We have solved the structure of Pseudomonas aeruginosa FabA with a substrate allowing detailed molecular insight into the interactions of the active site. This has allowed a detailed examination of the factors governing the second catalytic step. We have also determined the structure of FabA in complex with small molecules (so-called fragments). These small molecules occupy distinct regions of the active site and form the basis for a rational inhibitor design program.
