Diterpene modulator of macrophage phagosomal maturation
View Patent ↗Novel uses for diterpene modulators of macrophage phagosomal maturation are provided. The diterpene isotuberculosinol is used as an immune modulator, assay for pharmaceutical compositions and an isolated Mycobacterium tuberculosis labdane-related diterpenoid virulence factor. A method of treating Mycobacterium tuberculosis infectivity is further provided.
1. A method of identifying compounds which inhibit in vivo infection by Mycobacterium tuberculosis comprising:
providing cells infected with Mycobacterium tuberculosis pathogen;
introducing a compound to said cells; and
determining whether said compound inhibits MtHPS to arrest synthesis of isotuberculosinol in said pathogen and inhibit Mycobacterium tuberculosis replication and infection.
2. The method according to claim 1 wherein said synthesis is enzymatic and encoded by Rv3378c.
3. An assay for identifying drug candidates capable of inhibiting isotuberculosinol synthesis to decrease Mycobacterium tuberculosis pathogenicity, comprising:
providing cells infected with Mycobacterium tuberculosis pathogen; and
administering a drug candidate to said cells to assay for arrest in isotuberculosinol synthesis within Mycobacterium tuberculosis pathogen.
4. The assay according to claim 3 wherein said arrest in isotuberculosinol synthesis is caused by an interaction with a class I or II diterpene cyclase.
5. The assay according to claim 3 wherein said synthesis of isotuberculosinol is enzymatic synthesis encoded by Rv3378c.
6. The assay according to claim 3 wherein said drug candidate is a diterpene cyclase antagonist or inhibitor.
7. The assay according to claim 3 wherein Mg 2+ concentrations in said cells is altered.
8. The assay according to claim 3 wherein said assay tests whether said drug candidate inhibits or enhances the synthesis of isotuberculosinol and wherein said drug candidate is identified as an antagonist or agonist.