RESUMEN
A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2, 3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6. 3 µM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
Asunto(s)
Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Inhibidores de Proteínas Quinasas , Salicilanilidas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Bacillus subtilis/enzimología , Bacillus subtilis/metabolismo , Bacillus subtilis/fisiología , Evaluación Preclínica de Medicamentos , Farmacorresistencia Microbiana , Enterococcus faecium/efectos de los fármacos , Enterococcus faecium/enzimología , Enterococcus faecium/genética , Enterococcus faecium/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bacterias Grampositivas/enzimología , Bacterias Grampositivas/fisiología , Luciferasas/genética , Luciferasas/metabolismo , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Fosforilación , Proteínas Quinasas/genética , Salicilanilidas/química , Salicilanilidas/farmacología , Esporas Bacterianas/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Vancomicina/farmacologíaRESUMEN
Observations of silicone granuloma formation and migration of silicone to regional lymph nodes have indicated a need for more research into the possible immunological responses to silicone. The present study was undertaken to assess the effect of injected silicone particles on the ability of splenic macrophages to produce interleukin 1 (IL-1) and to determine the relative quantities produced. Lewis rats were divided into 4 groups: Group 1 animals (n = 3) were injected subcutaneously with sterile saline (2.5 ml) and served as control animals; Group 2 animals (n = 3) also served as control subjects, but macrophages isolated from these animals were exposed to lipopolysaccharide (LPS); Group 3 animals (n = 3) were injected subcutaneously with Freund's complete adjuvant (FCA) (2.5 ml) to serve as FCA control animals; and Group 4 animals (n = 3) received a subcutaneous injection of a sonicated slurry of equal parts FCA and silicone (2.5 ml each). IL-1 production was not significantly increased in splenic macrophages from animals exposed to the silicone slurry (p greater than 0.20) 8 months after injection as compared with control animals or animals given FCA alone. Macrophages exposed to LPS, a known mitogen, had significantly elevated IL-1 production. Subcutaneously injected silicone particles did not elicit an increase in IL-1 production in rat macrophages.