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We recently reported on our success to generate deletion mutants of the genes encoding glutamate dehydrogenase (GDH) and glutamine oxoglutarate aminotransferase (GOGAT) in  M .  bovis BCG , despite their  in vitro  essentiality in  M .  tuberculosis . We could use these mutants to delineate the roles of GDH and GOGAT in mycobacterial nitrogen metabolism by using  M .  bovis  BCG as a model for  M .  tuberculosis  specifically. Here, we extended our investigation towards the involvement of GDH and GOGAT in other aspects of  M .  bovis  BCG physiology, including the use of glutamate as a carbon source and resistance to known phagosomal stresses, as well as in survival inside macrophages. We find that  gdh  is indispensable for the utilization of glutamate as a major carbon source, in low pH environments and when challenged with nitric oxide. On the other hand, the  gltBD  mutant had increased viability under low pH conditions and was unaffected by a challenge with nitric oxide. Strikingly, GDH was required to sustain  M .  bovis  BCG during infection of both murine RAW 264.7 and bone-marrow derived and macrophages, while GOGAT was not. We conclude that the catabolism of glutamate in slow growing mycobacteria may be a crucial function during infection of macrophage cells and demonstrate a novel requirement for  M .  bovis  BCG GDH in the protection against acidic and nitrosative stress. These results provide strong clues on the role of GDH in intracellular survival of  M .  tuberculosis , in which the essentiality of the  gdh  gene complicates knock out studies making the study of the role of this enzyme in pathogenesis difficult.

Glutamate Dehydrogenase Is Required by Mycobacterium bovis BCG for Resistance to Cellular Stress