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 1.0-5.0 μg/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.
Bibliographical noteFunding Information:
The authors are grateful to Dr. Nicole J. de Voogd, National Museum of Natural History, The Netherlands for identification of the sponge. The authors also thank to Dr. Takefumi Doi, Osaka University, for cooperation of preparing transformants in electroporation step. A.D.B. is supported by a grant from the Helen Hay Whitney Foundation. This study was financially supported by grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
- Anti-Mycobacterium tuberculosis
- Marine sponge