Halicyclamine A, a marine spongean alkaloid as a lead for anti-tuberculosis agent |
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Authors: | Arai Masayoshi Sobou Mari Vilchéze Catherine Baughn Anthony Hashizume Hiroyuki Pruksakorn Patamaporn Ishida Shunsuke Matsumoto Makoto Jacobs William R Kobayashi Motomasa |
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Affiliation: | Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan. |
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Abstract: | In the course of our search for anti-microbial agents against dormant Mycobacterium tuberculosis, halicyclamine A was re-discovered as a lead for anti-tuberculosis agent from a marine sponge of Haliclona sp. on the guidance of the constructed bioassay. Halicyclamine A showed growth inhibition against Mycobacterium smegmatis, Mycobacterium bovis BCG, and M. tuberculosis H37Ra with MICs in the range of 1.0-5.0microg/ml under both aerobic condition and hypoxic condition inducing dormant state. The growth-inhibitory activity of halicyclamine A was bactericidal, and halicyclamine A did not exhibit cross-resistance with the currently used anti-tuberculosis drugs of isoniazid, ethambutol, rifampicin, and streptomycin. Halicyclamine A has been isolated originally as one of the active constituents inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH). Then, in order to elucidate action-mechanism of halicyclamine A, we prepared IMPDH over-expressing strains of M. smegmatis. However, IMPDH was not target for halicyclamine A, because halicyclamine A showed same MIC value against the wild-type M. smegmatis and IMPDH over-expressing strains. |
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