Mycobacterial Siderophores: Assembly, Assembly Inhibition, and Role in Virulence

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Multidrug-resistant (MOR) tuberculosis (TB) is recognized as an emerging infectious disease and a major problem in global public health. MDR 44. tuberculosis is also classified as a Category C Priority Pathogen for biodefense research. The threat of MDR and extensively/extremely drug-resistant (XDR) TB outbreaks that are resistant to current anti-TB drugs, either due to natural emergence or bioterrorism, is an alarming scenario since untreated (or untreatable) TB carries a mortality rate of 40-60%. Public health preparedness for intractable TB cases requires the development of new chemotherapies that kill M. tuberculosis or impair its virulence or growth in the host. To this end, studies on M. tuberculosis biology are priorities of utmost importance as they may illuminate avenues to develop new chemotherapies. The long-term goal of this project is to elucidate the biosynthesis of mycobacterial siderophores (iron-scavenging compounds) that are required for multiplication of M. tuberculosis inside the macrophages of the host, an ability of (0. tuberculosis needed to produáe disease. We will pursue this goal through two specific aims: (1) To probe in vitro the enzymatic functions of the MbtABCDEF enzyme system in siderophore biosynthesis; and (2) To investigate the involvement of the genes in the mbt gene cluster in siderophore production using a genetic approach. These two aims are highly complementary, yet independent, and represent biochemical and genetic approaches, respectively, to study the biosynthesis of mycobacterial siderophores. The knowledge gained will shed light on unexplored aspects of mycobacterial siderophore biosynthesis. This project will revealed potential new targets for anti-tuberculosis drug development and thus it may illuminate novel avenues for developing drugs that may find a particularly important niche in therapeutic and/or prophylactic multi-drug treatments against MDRIXDR M. tuberculosis, which is a major threat to global public health and a potential agent for use in bioterrorism.