Mycobacterium tuberculosis (Mtb), a deadly pathogen, has scourged mankind for many centuries. Tuberculosis, the disease caused by this bacterium, remains a threat for global health. [1] Cholesterol utilization for nutrition is a key feature of many bacterial species, including the pathogenic mycobacterial species which have evolved to survive in niche environments. Steroid lipid binding cytochrome P450 (CYP) enzymes are involved in the initial steps of cholesterol degradation. CYP124, CYP125 and CYP142 enzymes have been reported to be involved in cholesterol and cholestenone oxidation and breakdown.[2] They hydroxylate cholesterol and cholestenone at a terminal methyl of the side chain. Interfering with this pathway will offer specific inhibitors, making the development of resistance difficult enabling the development of more effective strategies to block this essential activity. The CYP124 enzymes can also catalyze the terminal hydroxylation of methyl-branched fatty acids. The counterparts to these enzymes from other Mycobacterium species (M. marinum) are studied to compare their structure and function versus M. tuberculosis. [3] The goal is to determine if new cholesterol derived inhibitors are effective on all of these P450 enzymes across different bacterial species. This knowledge will enable the inhibitors to be designed for specific species of mycobacteria for example M. tuberculosis and M. ulcerans. Crystal structures of the enzymes with substrates and inhibitors will reveal the relationship between enzyme structure and their activity for cholesterol and cholestenone oxidation. These enzymes are therefore potential therapeutic targets, and their inhibition will enable applications for the treatment of diseases such as tuberculosis and Buruli ulcer.
References
[1] M. D. Driscoll, K. J. McLean, C. Levy, N. Mast, I. A. Pikuleva, P. Lafite, S. E. Rigby, D. Leys and A. W. Munro, J Biol Chem 2010, 285, 38270-38282.
[2] D. J. Frank, Y. Madrona and P. R. Ortiz de Montellano, J Biol Chem 2014, 289, 30417-30425.
[3] S. A. Child, A. Ghith, J. B. Bruning and S. G. Bell, J Inorg Biochem 2020, 209, 111116.