Abstract:
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is second only to HIV as the leading infectious killer of adults worldwide. It also accounts for more deaths among women than all other causes of maternal mortality combined and is the leading infectious cause of death among people with HIV/AIDS. Emergence of multiand extensively-drug resistant strains of Mtb, the growing global HIV/AIDS pandemic and a lack of appropriate drugs to target persistent disease are amongst the reasons for seeking new drugs against TB. PA-824 is a promising anti-TB compound currently undergoing clinical trial with the Global Alliance for TB Drug Development. PA-824 exhibits potent bactericidal activity against both growing and dormant Mtb and requires reductive, bacterial activation. The first step in PA-824 activation is catalysed by FGD1, which is an F₄₂₀-dependent glucose-6-phosphate dehydrogenase, providing reduced F₄₂₀ for this activation. The second step is believed to be catalysed by a nitroreductase, which uses the reduced F420 to reduce the nitro group of PA-824. This project aimed to characterize the structure and function of the annotated family of nitroreductases, F42o-dependent glucose-6-phosphate dehydrogenase family (FGD1 and FGD2), and Rv3547, in order to better understand their role in PA-824 activation and their relevance to Mtb persistence.
