Isotuberculosinol: An immunomodulatory diterpenoid from Mycobacterium tuberculosis

Mycobacterium tuberculosis ( Mtb ) is the causative agent of the human disease Tuberculosis, and remains a worldwide health threat responsible for ~1.7 million deaths annually. During infection, Mtb prevents acidification of the engulfing phagosome, thus blocking endocytic progression and eventually leading to stable residence. Notably, a genetic screen for mutants specifically deficient in this early step of the infection process highlighted a small operon that appeared to be involved in isoprenoid/terpenoid biosynthesis. Based on this provocative finding, a number of groups, including my own, have investigated the corresponding natural product. While we had initially characterized this as a tricyclic diterpene olefin, we have corrected this to the bicyclic diterpenoid alcohol, isotuberculosinol (isoTb), originally suggested by Nakano and Hoshino. Our results further demonstrate that isoTb alone exhibits biological activity consistent with the hypothetical role in early arrest of phagosome maturation indicated by the original genetic screen. On this basis, we have investigated inhibitors of the relevant diterpene synthases, using compounds developed against the corresponding plant enzymes, and have identified high affinity inhibitors, as well as generalized structural features useful in such efforts. In addition, we have provided evidence indicating that the depletion of Mg 2+ experienced by the bacterium upon phagosomal engulfment triggers Mtb production of isoTb. More speculatively, we note that the ability to produce isoTb is unique to Mtb , and appears to have been lost in even the closely related M. bovis , and hypothesize that isoTb might be involved in the difference in host specificity of Mtb relative to other mycobacteria.