A Nudix Hydrolase Necessary for Mycobacterium Tuberculosis Survival under Oxidative Stress

Despite a constant decrease in tuberculosis (TB) incidence rates, nearly two billion people worldwide are estimated to have latent TB. Five to ten percent of people with latent TB will develop the active form of the disease. Of the estimated 8.6 million new cases of active TB in 2012, 1.3 million people died of the disease and 450,000 developed multidrug-resistant TB. Resistance to oxidative stress is essential for Mycobacterium tuberculosis (Mtb) survival in host macrophages and the onset of latent TB infection. We have identified a Nudix (nucleoside diphosphate-linked moiety X) hydrolase, RenU, necessary for Mtb survival in oxidative stress environments. We show that RenU preferentially degrades adenosine derivatives over other nucleoside derivatives. Through a novel fluorescence based assay, we also determined that RenU prefers NADH as a substrate over NAD. Furthermore, we show that RenU is required for Mtb survival within macrophages. The link between RenU, NADH, and Mtb survival warrants further investigation as it could be the basis for novel therapeutic approaches to prevent and combat latent TB.