NAD+ auxotrophy is bacteriocidal for the tubercle bacilli.

Abstract

The human tubercle bacillus Mycobacterium tuberculosis can synthesize NAD(+) using the de novo biosynthesis pathway or the salvage pathway. The salvage pathway of the bovine tubercle bacillus Mycobacterium bovis was reported defective due to a mutation in the nicotinamidase PncA. This defect prevents nicotinic acid secretion, which is the basis for the niacin test that clinically distinguishes M. bovis from M. tuberculosis. Surprisingly, we found that the NAD(+)de novo biosynthesis pathway (nadABC) can be deleted from M. bovis, demonstrating a functioning salvage pathway. M. bovisDeltanadABC fails to grow in mice, whereas M. tuberculosisDeltanadABC grows normally in mice, suggesting that M. tuberculosis can acquire nicotinamide from its host. The introduction of M. tuberculosis pncA into M. bovisDeltanadABC is sufficient to fully restore growth in a mouse, proving that the functional salvage pathway enables nicotinamide acquisition by the tubercle bacilli. This study demonstrates that NAD(+) starvation is a cidal event in the tubercle bacilli and confirms that enzymes common to the de novo and salvage pathways may be good drug targets.