RESUMEN
Multidrug-resistant bacterial infections have become a global threat. We recently disclosed that the known IKK-ß inhibitor IMD-0354 and subsequent analogues abrogate colistin resistance in several Gram-negative strains. Herein, we report the activity of a second-generation library of IMD-0354 analogues incorporating a benzimidazole moiety as an amide isostere. We identified several analogues that show increased colistin potentiation activity against Gram-negative bacteria.
Asunto(s)
Colistina , Salicilanilidas , Antibacterianos/farmacología , Bencimidazoles/farmacología , Colistina/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Hypertension affects more than 1.5 billion people worldwide but the precise cause of elevated blood pressure (BP) cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers BP in the majority of patients with hypertension. Despite its apparent role in hypertension pathogenesis, the key cellular targets of the RAS that control BP have not been clearly identified. Here we demonstrate that RAS actions in the epithelium of the proximal tubule have a critical and nonredundant role in determining the level of BP. Abrogation of AT(1) angiotensin receptor signaling in the proximal tubule alone is sufficient to lower BP, despite intact vascular responses. Elimination of this pathway reduces proximal fluid reabsorption and alters expression of key sodium transporters, modifying pressure-natriuresis and providing substantial protection against hypertension. Thus, effectively targeting epithelial functions of the proximal tubule of the kidney should be a useful therapeutic strategy in hypertension.
