RESUMEN
Two series of clarithromycin and azithromycin derivatives with terminal 6-alkylquinolone-3-carboxylic unit with central ether bond in the linker were prepared and tested for antimicrobial activity. Quinolone-linker intermediates were prepared by Sonogashira-type C(6)-alkynylation of 6-iodo-quinolone precursors. In the last step, 4'' site-selective acylation of 2'-protected macrolides was completed with the EDC reagent, which selectively activated a terminal, aliphatic carboxylic group in dicarboxylic intermediates. Antimicrobial activity of the new series of macrolones is discussed. The most potent compound, 4''-O-{6-[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydroquinolin-6-yl)-propoxy]-hexanoyl}-azithromycin (10), is highly active against bacterial respiratory pathogens resistant to macrolide antibiotics and represents a promising lead for further investigation.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Azitromicina/análogos & derivados , Claritromicina/análogos & derivados , Macrólidos/síntesis química , Quinolonas/síntesis química , Antibacterianos/química , Azitromicina/química , Azitromicina/farmacología , Claritromicina/química , Claritromicina/farmacología , Humanos , Macrólidos/química , Macrólidos/farmacología , Pruebas de Sensibilidad Microbiana , Quinolonas/química , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
Pantothenate kinase (CoaA) catalyzes the first step of the coenzyme A biosynthetic pathway. Here we report the identification of the Staphylococcus aureus coaA gene and characterization of the enzyme. We have also identified a series of low-molecular-weight compounds which are effective inhibitors of S. aureus CoaA.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/enzimología , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , Coenzima A/biosíntesis , ADN Bacteriano/química , ADN Bacteriano/genética , Humanos , Concentración 50 Inhibidora , Cinética , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Ácido Pantoténico/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Filogenia , Alineación de Secuencia , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Células Tumorales CultivadasRESUMEN
Homologues of Escherichia coli bacA, encoding extremely hydrophobic proteins, were identified in the genomes of Staphylococcus aureus and Streptococcus pneumoniae. Allelic replacement mutagenesis demonstrated that the gene is not essential for in vitro growth in either organism, and the mutants showed no significant changes in growth rate or morphology. The Staph. aureus bacA mutant showed slightly reduced virulence in a mouse model of infection and an eightfold increase in bacitracin susceptibility. However, a Strep. pneumoniae bacA mutant was highly attenuated in a mouse model of infection, and demonstrated an increase in susceptibility to bacitracin of up to 160000-fold. These observations are consistent with the previously proposed role of BacA protein as undecaprenol kinase.
