Promising Tuberculosis Drug Destroys Dormant Bacteria

A drug currently in clinical trails against multidrug resistant tuberculosis has been shown to kill the dormant form of Mycobacterium tuberculosis that lingers for years in the lungs of asymptomatic individuals.

An estimated one-third of the world's population is latently infected with M. tuberculosis. These non-replicating, dormant bacilli are not susceptible to conventional antituberculosis drugs, such as isoniazid.

Investigators at Johnson and Johnson (Beerse, Belgium) have been studying the experimental diarylquinoline drug R207910, which they had found to be an inhibitor of the enzyme ATP synthase. They reasoned that even dormant bacteria would require some small amount of ATP synthesis to survive.

The investigators reported in the September 12, 2008, issue of the Journal of Biological Chemistry (JBC) that despite a transcriptional downregulation of the ATP synthase operon and significantly lower cellular ATP levels, dormant mycobacteria did possess residual ATP synthase enzymatic activity. This activity was blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect.

The authors concluded that, "This residual ATP synthase activity was indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguished them entirely from the current antituberculosis drugs and underlined the potential of R207910 to shorten tuberculosis treatment."

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