Investigating the anti-tubercular mechanism of action of pseudopteroxazole: An activity-based photolabeling approach
Mycobacterium tuberculosis (MTB), the etiologic agent of tuberculosis disease, causes nearly two million deaths annually and has established a latent infection in one third of the human population.1 Pseudopteroxazole (Ptx), a diterpene isolated from the coral Pseudopterogorgia elisabethae,2 exhibits promising activity in a model of non-replicating persistent MTB and against several drug-resistant MTB strains.3,4 Considering the structural novelty of Ptx, as well as its efficacy against drug-resistant MTB strains, we hypothesize that Ptx may exert its activity through a unique mechanism of action (MoA). The aim of this research is to identify the MoA of Ptx by pursuing two complementary strategies. The mode of action of Ptx will be determined by measuring the incorporation of tritiated precursors into bacterial macromolecules. Meanwhile, the cellular target of Ptx will be identified using an activity-based photolabeling strategy by employing semisynthetic photoaffinity probes.
1) Barry, C.E.; et al. Nat. Rev. Microbiol. 2009, 7, 845. 2) Rodríguez, A.D.; et al. Org. Lett. 1999, 1, 527. 3) McCulloch, M.W.B.; et al., J. Nat. Prod. 2011, 74, 2250. 4) McCulloch, M.W.B.; Haltli, B.; Marchbank, D.H.; Kerr, R.G. Mar. Drugs 2012 [submitted].