Tuberculosis (TB) is caused by the human pathogen Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), 10 million new TB cases are reported worldwide annually and 1.7 million people died in 2016 from TB infection. The emergence of resistant Mtb strains to one or more first-line anti-TB agents, as well as the fatal synergistic action of TB with AIDS, has prompted the development and marketing authorization of new drugs for TB.
Genome mapping of Mtb revealed that the genome contains genes encoding for a high number of cytochrome P450 enzymes (CYPs or P450s) that are involved in very specific and physiologically relevant pathways for the bacteria. Therefore, cytochrome P450 enzymes are investigated as targets for novel therapeutic agents. Sandra Ortega Ugalde and her AIMMS colleagues identified the reaction catalyzed by one of these CYPs, CYP130A1, shedding light into its physiological role. Furthermore, catalytic activity of mycobacterial CYPs is dependent on electron transfer from a NAD (P)H-ferredoxin-reductase and a ferredoxin. Ortega and her colleagues have improved the basic understanding of the selectivity, biochemical properties, and function of the iron-sulfur cluster-containing ferredoxin proteins in Mtb essential for the reconstitution of the cognate CYP catalytic system to aid in the development of new antibiotics. Finally, they are also conducting collaborative studies to synthetize specific and potent inhibitors for some of these essential CYPs, aiming for a synergistic effect with the available anti-TB drugs and avoiding off-target toxicities by interaction with human CYPs.