RESUMEN
3-(Phenethylamino)demethyl(oxy)aaptamine (1) was re-discovered from the marine sponge of Aaptos sp. as an anti-dormant mycobacterial substance through the bioassay-guided separation. Compound 1 showed potent anti-microbial activity against Mycobacterium bovis BCG with a minimum inhibitory concentration of 0.75 µg/mL under both aerobic conditions and hypoxic conditions inducing dormant state. Compound 1 was also effective against pathogenic M. tuberculosis strains including clinical multidrug-resistant strains. Furthermore, the successful total syntheses of 1 and its analog 3-aminodemethyl(oxy)aaptamine (2) afford sufficient quantities for further biological studies.
RESUMEN
In the course of our search for anti-dormant Mycobacterial substances, nybomycin (1) was re-discovered from the culture broth of a marine-derived Streptomyces sp. on the bioassay-guided separation. Compound 1 showed anti-microbial activity against Mycobacterium smegmatis and Mycobacterium bovis BCG with the MIC of 1.0µg/mL under both actively growing aerobic conditions and dormancy inducing hypoxic conditions. Compound 1 is also effective to Mycobacterium tuberculosis including the clinically isolated strains. The mechanistic analysis indicated that 1 bound to DNA and induces a unique morphological change to mycobacterial bacilli leading the bacterial cell death.
Asunto(s)
Antituberculosos/farmacología , ADN Bacteriano/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Streptomyces/química , Antituberculosos/química , Antituberculosos/aislamiento & purificación , Organismos Acuáticos , Técnicas de Cultivo de Célula , Cósmidos/química , Cósmidos/metabolismo , ADN Bacteriano/química , Farmacorresistencia Bacteriana/genética , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Mycobacterium bovis/efectos de los fármacos , Mycobacterium bovis/genética , Mycobacterium bovis/metabolismo , Mycobacterium bovis/ultraestructura , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/metabolismo , Mycobacterium smegmatis/ultraestructura , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/ultraestructura , Quinolonas/química , Quinolonas/aislamiento & purificación , Quinolonas/farmacología , Streptomyces/metabolismoRESUMEN
A new aaptamine class alkaloid, designated 2-methoxy-3-oxoaaptamine (1), together with seven known aaptamines (2-8) were isolated from a marine sponge of Aaptos sp. as anti-mycobacterial substances against active and dormant bacilli. The chemical structure of 1 was determined on the basis of spectroscopic analysis. Compound 1 was anti-mycobacterial against Mycobacterium smegmatis in both active growing and dormancy-inducing hypoxic conditions with a minimum inhibitory concentration (MIC) of 6.25 µg/ml, and compounds 2, 5, 6, and 7 showed anti-mycobacterial activities under hypoxic condition selectively, with MIC values of 1.5-6.25 µg/ml.
