RESUMEN
Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the beta-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications.
Asunto(s)
Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/metabolismo , Membrana Celular/metabolismo , Péptidos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/metabolismo , Animales , Antibacterianos/síntesis química , Antibacterianos/metabolismo , Péptidos Catiónicos Antimicrobianos/química , Proteínas de la Membrana Bacteriana Externa/química , Proteínas de la Membrana Bacteriana Externa/genética , Diseño de Fármacos , Farmacorresistencia Bacteriana/genética , Genes Bacterianos , Lipopolisacáridos/metabolismo , Ratones , Pruebas de Sensibilidad Microbiana , Imitación Molecular , Mutación , Biblioteca de Péptidos , Péptidos/síntesis química , Péptidos/química , Péptidos/metabolismo , Estructura Terciaria de Proteína , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/ultraestructura , Sepsis/tratamiento farmacológico , Sepsis/microbiologíaRESUMEN
An ortho-metalation method for free ferrocenyl alcohols has been developed, which allows preparation of planar chiral ferrocene derivatives with high yields and diastereoselectivities.
Asunto(s)
Alcoholes/síntesis química , Compuestos Ferrosos/síntesis química , Litio/química , Metalocenos , Compuestos Organometálicos/química , EstereoisomerismoRESUMEN
Iminosugars, featuring a basic nitrogen at the hetero atom position in carbohydrate rings, gain increasing interest in the search for novel approaches towards cancer drug development. This compound class is known as competitive inhibitors of carbohydrate manipulation enzymes, such as glycosidases, which are involved in tumor cell invasion and migration. Such enzymes are also responsible for the attachment of oligosaccharides to the cell surface of tumor cells, displayed as glycoproteins, glycolipids, and proteoglycans, which play an important role in malignant phenotype and tumor growth. Furthermore, cancer cells show an extremely active lysosomal system which is reflected by enhancement of glycoprotein turnover. Iminosugars were found to interact with glycosyl hydrolases responsible for this kind of action in cancer cells and thus open a new compound class in the research field of finding new anti-cancer activities. This review will focus on the role of iminosugars in cancer therapy and will give an overview of their properties.