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
A class of antibacterials has been discovered that inhibits the growth of Gram-positive pathogenic bacteria. RWJ-49815, a representative of a family of hydrophobic tyramines, in addition to being a potent bactericidal Gram-positive antibacterial, inhibits the autophosphorylation of kinase A of the KinA::Spo0F two-component signal transduction system in vitro. Analogs of RWJ-49815 vary greatly in their ability to inhibit growth of bacteria and this ability correlates directly with their activity as kinase A inhibitors. Compared with the potent quinolone, ciprofloxacin, RWJ-49815 exhibits reduced resistance emergence in a laboratory passage experiment. Inhibition of the histidine protein kinase::response regulator two-component signal transduction pathways may present an opportunity to depress chromosomal resistance emergence by targeting multiple proteins with a single inhibitor in a single bacterium. Such inhibitors may represent a class of antibacterials that potentially may represent a breakthrough in antibacterial therapy.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Inhibidores Enzimáticos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Guanidinas/farmacología , Proteínas Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Compuestos de Tritilo/farmacología , Relación Dosis-Respuesta a Droga , Farmacorresistencia Microbiana , FosforilaciónRESUMEN
This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel (1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium.
Asunto(s)
Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Salicilanilidas/farmacología , Antibacterianos/química , Farmacorresistencia Microbiana , Enterococcus faecium/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Fosforilación , Salicilanilidas/química , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
This study determined the rate of anterior chamber aerobic bacterial contamination in 103 eyes that had uncomplicated posterior chamber phacoemulsification. Anterior chamber fluid was aspirated on completion of surgery. Cultures of sterile balanced salt solution served as a control. Of 103 anterior chamber cultures, 4 (3.9%) showed contamination; however, 3 of 103 control cultures (2.9%) also grew micro-organisms. These findings suggest a very low rate of aerobic bacterial contamination after uncomplicated phacoemulsification and underscore the importance of control cultures when determining contamination rates.
Asunto(s)
Cámara Anterior/microbiología , Facoemulsificación , Anciano , Líquidos Corporales/microbiología , Femenino , Humanos , Masculino , Micrococcus/aislamiento & purificación , Facoemulsificación/efectos adversos , Staphylococcus/aislamiento & purificaciónRESUMEN
A series of close analogues of the potent, long-acting cardiotonic bemoradan (2a) was synthesized and examined in both in vitro and in vivo test systems. Changing the oxygen heteroatom at the 1-position of the benzoxazine ring of bemoradan to sulfur gave 4a, a more potent enzyme inhibitor and in vivo cardiotonic compound by the iv route. Intraduodenal administration of bemoradan, however, showed a superior response compared to its sulfur analogue, possibly due to oxidation of sulfur followed by a facile Pummerer rearrangement. Model studies were performed to examine the effect of the oxidation state of sulfur. Lack of a heteroatom at the 1-position, 3a (Y-590), afforded a compound with activity and potency very similar to those of bemoradan while the 1-selena compound gave a much less potent analogue 5. Analogues having a methyl group on the 4-nitrogen (2b, 3b, and 4b) were less potent than the desmethyl compounds, but all of these compounds have potent PDE III inhibiting activity and the ability to increase cardiac force in an anesthetized dog preparation when given iv.
Asunto(s)
Cardiotónicos/síntesis química , Oxazinas/química , Oxazinas/síntesis química , Piridazinas/química , Piridazinas/síntesis química , Animales , Benzoxazinas , Cardiotónicos/química , Cardiotónicos/farmacología , Perros , Corazón/efectos de los fármacos , Miocardio/enzimología , Oxazinas/farmacología , Piridazinas/farmacología , Relación Estructura-ActividadRESUMEN
Results of a multicentre, controlled, comparative study of two daily care regimens for rigid gas-permeable contact lenses are described. Whereas both regimens were generally effective and safe for the 69 patients wearing the Boston Lens, the Barnes-Hind regimen showed clinically and statistically significant advantages over the Boston Lens regimen: the proportions of patients in the Barnes-Hind group with corneal staining or palpebral conjunctival injection were reduced during the study and were lower on several occasions than the proportions of the Boston group.