TY - JOUR
T1 - NAD+ auxotrophy is bacteriocidal for the tubercle bacilli
AU - Vilchèze, Catherine
AU - Weinrick, Brian
AU - Wong, Ka Wing
AU - Chen, Bing
AU - Jacobs, William
PY - 2010/4
Y1 - 2010/4
N2 - Summary 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. bovis ΔnadABC fails to grow in mice, whereas M. tuberculosis ΔnadABC grows normally in mice, suggesting that M. tuberculosis can acquire nicotinamide from its host. The introduction of M. tuberculosis pncA into M. bovis ΔnadABC 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.
AB - Summary 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. bovis ΔnadABC fails to grow in mice, whereas M. tuberculosis ΔnadABC grows normally in mice, suggesting that M. tuberculosis can acquire nicotinamide from its host. The introduction of M. tuberculosis pncA into M. bovis ΔnadABC 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.
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U2 - 10.1111/j.1365-2958.2010.07099.x
DO - 10.1111/j.1365-2958.2010.07099.x
M3 - Article
C2 - 20199601
AN - SCOPUS:77951165552
SN - 0950-382X
VL - 76
SP - 365
EP - 377
JO - Molecular Microbiology
JF - Molecular Microbiology
IS - 2
ER -