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1.
mBio ; 6(3): e00647, 2015 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-26106079

RESUMEN

UNLABELLED: Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N'-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N'-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE: Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.


Asunto(s)
Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Compuestos de Bencilo/aislamiento & purificación , Compuestos de Bencilo/farmacología , Vías Biosintéticas/efectos de los fármacos , Hongos/efectos de los fármacos , Esfingolípidos/biosíntesis , Animales , Antifúngicos/efectos adversos , Antifúngicos/toxicidad , Compuestos de Bencilo/efectos adversos , Compuestos de Bencilo/toxicidad , Candidiasis/tratamiento farmacológico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Sinergismo Farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Hongos/citología , Hongos/metabolismo , Hongos/fisiología , Macrófagos/efectos de los fármacos , Macrófagos/fisiología , Ratones , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Microscopía Electrónica de Transmisión , Estructura Molecular , Esfingolípidos/antagonistas & inhibidores , Resultado del Tratamiento
2.
Am Heart J ; 145(2): e8, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12595863

RESUMEN

BACKGROUND: Extra-lipid effects of statins, such as anti-inflammatory actions, may contribute to their clinical benefit. These effects, with important implications for the concept of a statin "class effect," may be drug specific or may be related to the extent of lipid lowering. METHODS: We randomized 130 patients to treatment with either atorvastatin (80 mg daily, n = 63) or pravastatin (40 mg daily, n = 67), and measured serum lipids, C-reactive protein, and fibrinogen at baseline and after 3 months of therapy. RESULTS: Mean C-reactive protein (CRP) levels were significantly reduced in both groups, with a 36% reduction in the atorvastatin group (0.39 +/- 0.36 to 0.25 +/- 0.27, P =.001) and a 22% reduction observed in the pravastatin group (0.40 +/- 0.33 to 0.31 +/- 0.32, P =.003). A reduced or unchanged CRP level was seen in 67.2% of pravastatin-treated patients (45/67) and 73% of atorvastatin- treated patients (46/63) (P =.47). There was no difference between drugs in either the absolute or relative reductions in CRP levels. However, whereas the reduction of CRP with pravastatin was unrelated to the degree of low-density lipoprotein reduction (r = -.05, P =.69), atorvastatin-induced CRP reductions correlated directly to the change in low-density lipoprotein-C (r =.33, P =.009). CONCLUSIONS: High-dose atorvastatin and pravastatin both reduce CRP levels. However, whereas pravastatin's effect on CRP is independent of lipid-lowering efficacy, these data suggest that lipid-dependent mechanisms are, at least in part, active in atorvastatin-treated patients.


Asunto(s)
Anticolesterolemiantes/farmacología , Proteína C-Reactiva/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Pravastatina/farmacología , Pirroles/farmacología , Adulto , Atorvastatina , Proteína C-Reactiva/análisis , Arterias Carótidas/anatomía & histología , Arterias Carótidas/efectos de los fármacos , LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Femenino , Fibrinógeno/análisis , Fibrinógeno/efectos de los fármacos , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Túnica Íntima/anatomía & histología , Túnica Íntima/efectos de los fármacos
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