Investigation of M. tuberculosis Cytochrome P450 Involvement in Cholesterol Utilization

Sponsor: Heiser Program for Research in Leprosy

Location(s): United States


Mycobacterium tuberculosis is the causative agent of human tubercular infection (tuberculosis) that, even today, poses a great threat to global human health. More than two billion people (a third of the world population) are infected latently with the bacterium, and of those individuals, ~10% will develop active tuberculosis infections during their lifetime. Currently, more than two million lives are claimed annually due to active M. tuberculosis infections . Among first world countries, the spread of M. tuberculosis has been kept mostly under control, but there has been a resurgence in developing countries in large part due to the emergence of multidrug-resistant bacterial strains that make the traditional frontline antibiotics less effective. Efforts continue on many fronts to understand this complex pathogen with a focus on identification of new drug targets.

To proliferate within the macrophages, M. tuberculosis cells undergo a shift in metabolism from using carbohydrates to primarily utilizing host lipids. Sequencing of the M. tuberculosis genome revealed at least 250 genes predicted to be involved in lipid metabolism. A cholesterol catabolism cluster of 51 genes was recently identified in the genome of the M. tuberculosis-related actinomycete Rhodococcus jostti RHA1. This region corresponds to the 82-gene cluster of M. tuberculosis that includes genes for proteins involved in both cholesterol uptake and degradation, suggesting that M. tuberculosis can utilize cholesterol for growth during infection. The steroid transporter Mce4 was shown to be important for the uptake of cholesterol in both R. jostii RHA1 and M. tuberculosis, and there is a growing body of evidence that M. tuberculosis can utilize cholesterol as a source of carbon and energy by degrading both the rings and the side chain during infection