ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Antitubercular Agents/pharmacology , DNA, Bacterial/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Streptomyces/chemistry , Antitubercular Agents/chemistry , Antitubercular Agents/isolation & purification , Aquatic Organisms , Cell Culture Techniques , Cosmids/chemistry , Cosmids/metabolism , DNA, Bacterial/chemistry , Drug Resistance, Bacterial/genetics , Microbial Sensitivity Tests , Microbial Viability/drug effects , Mycobacterium bovis/drug effects , Mycobacterium bovis/genetics , Mycobacterium bovis/metabolism , Mycobacterium bovis/ultrastructure , Mycobacterium smegmatis/drug effects , Mycobacterium smegmatis/genetics , Mycobacterium smegmatis/metabolism , Mycobacterium smegmatis/ultrastructure , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/metabolism , Mycobacterium tuberculosis/ultrastructure , Quinolones/chemistry , Quinolones/isolation & purification , Quinolones/pharmacology , Streptomyces/metabolismABSTRACT
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.