Menaquinone Biosynthesis: A Drug Target in Gram-Positive Bacteria

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 DESCRIPTION (provided by applicant): Many Gram-positive bacteria including Mycobacterium tuberculosis, Listeria monocytogenes and Staphylococcus aureus are pathogens with significant impact on human suffering, and potentially, bioterrorism worldwide. With increasing levels of drug resistance in virtually all pathogens there is significant interest n the development of new drugs. The World Health Organization (WHO) published a goal of having 21 new or repurposed anti-tuberculosis drugs in Phase 1 clinical trials by 2015. Reaching this goal will require a tremendous investment in effort and money; however, new drugs to combat these pathogens would help reduce human suffering and potentially counter the threat of bioterrorism. The pathogens mentioned above are obligate aerobic Gram-positives, utilizing menaquinone as the sole lipoquinone in their electron transport chain. This suggests that menaquinone synthesis may present a potential drug target in all. Although the work proposed here is applicable to most Gram-positive organisms, emphasis has been placed on M. tuberculosis. Thus, the overriding goal of this project is to identify new compounds that have the potential for entering the drug development pipeline and helping to meet the WHO goals. We have previously demonstrated that menaquinone synthesis is a viable "druggable" target and identified enzymes involved in menaquinone synthesis in mycobacteria that were previously unknown and, which may also provide potential new drug targets. In this project we will refine our lead compounds via medicinal chemistry guided by enzyme kinetics, evaluate mechanisms of action for these new compounds and study the physiological importance of novel enzymes identified to be involved in mycobacterial menaquinone synthesis. If funded, the project will generate new and improved anti-TB compounds based on our current lead compound, identify new pharmacophores that inhibit various aspects of oxidative phosphorylation, identify previously unknown drug targets and significantly advance our understanding of how mycobacteria are able to regulate oxygen consumption and ATP synthesis in the hypoxic conditions found in the granulomas of infected lungs.