RESUMEN
The antibacterial activities of cationic steroid antibiotics and cationic peptide antibiotics have been compared. Depolarization of bacterial membranes, activation of bacterial stress-related gene promoters, and changes in bacterial morphologies caused by these antibiotics suggest that cationic steroid and peptide antibiotics share mechanistic aspects. Modified cationic steroid antibiotics display improved selectivity for prokaryotic cells over eukaryotic cells presumably due to increased charge recognition.
Asunto(s)
Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Esteroides/farmacología , Proteínas de Xenopus , Secuencia de Aminoácidos , Antibacterianos/síntesis química , Antibacterianos/química , Péptidos Catiónicos Antimicrobianos/química , Cationes , Membrana Celular/efectos de los fármacos , Recuento de Colonia Microbiana , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/crecimiento & desarrollo , Genes Bacterianos , Mediciones Luminiscentes , Pruebas de Sensibilidad Microbiana , Micrococcus luteus/efectos de los fármacos , Micrococcus luteus/ultraestructura , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/crecimiento & desarrollo , Espectrometría de Fluorescencia , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrollo , Esteroides/síntesis química , Esteroides/química , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/crecimiento & desarrolloRESUMEN
Cationic steroid antibiotics have been developed that display broad-spectrum antibacterial activity. These compounds are comprised of steroids appended with amine groups arranged to yield facially amphiphilic morphology. Examples of these antibiotics are highly bactericidal, while related compounds effectively permeabilize the outer membranes of Gram-negative bacteria sensitizing these organisms to hydrophobic antibiotics. Cationic steroid antibiotics exhibit various levels of eukaryote vs. prokaryote cell selectivity, and cell selectivity can be increased via charge recognition of prokaryotic cells. Studies of the mechanism of action of these antibiotics suggest that they share mechanistic aspects with cationic peptide antibiotics.
Asunto(s)
Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Antibacterianos/química , Antibacterianos/farmacocinética , Péptidos Catiónicos Antimicrobianos/metabolismo , Péptidos Catiónicos Antimicrobianos/farmacocinética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Colestanoles/farmacocinética , Hemólisis , Pruebas de Sensibilidad Microbiana , Modelos Estructurales , Polimixina B/farmacocinética , Esteroides/química , Esteroides/clasificación , Esteroides/farmacologíaRESUMEN
An efficient two-step procedure is described to convert the Biginelli 3,4-dihydropyrimidin-2(1H)-one to various multifunctionalized pyrimidines via the Kappe dehydrogenation and a new mild PyBroP-mediated coupling with C, N, O, and S nucleophiles, which provides a readily accessible multifunctionalized pyrimidine template for diversity-oriented synthesis.