Flexible nitrogen utilisation by the metabolic generalist pathogen Mycobacterium tuberculosis

Bacterial metabolism is fundamental to survival and pathogenesis. We explore how Mycobacterium tuberculosis utilises amino acids as nitrogen sources, using a combination of bacterial physiology and stable isotope tracing coupled to mass spectrometry metabolomics methods. Our results define core properties of the nitrogen metabolic network from M. tuberculosis, such as: (i) the lack of homeostatic control of certain amino acid pool sizes; (ii) similar rates of utilisation of different amino acids as sole nitrogen sources; (iii) improved nitrogen utilisation from amino acids compared to ammonium; and (iv) co-metabolism of nitrogen sources. Finally, we discover that alanine dehydrogenase is involved in ammonium assimilation in M. tuberculosis, in addition to its essential role in alanine utilisation as a nitrogen source. This study represents the first in-depth analysis of nitrogen source utilisation by M. tuberculosis and reveals a flexible metabolic network with characteristics that are likely a product of evolution in the human host.
eLife digest Tuberculosis is an infectious disease caused by a bacterium called Mycobacterium tuberculosis. It is currently the leading cause of death by a single microbe worldwide, claiming the lives of 1.5 million people annually. The disease is difficult to cure, as many strains of the bacterium have developed resistance to the main drugs used to treat the infection. This leaves physicians with few options to treat tuberculosis and control its spread. The spread of these drug-resistant strains is a major global public health problem. New strategies that do not lead to drug resistance are needed. One possibility would be to starve the bacterium. Like all living things, M. tuberculosis must eat to survive and spread. Right now, scientists do not know much about how this microbe eats. However, they do know that it needs nitrogen – an essential part of DNA, RNA, and proteins – to survive. Most bacteria like to consume ammonium as their main nitrogen source, but they may also use select amino acids as a nitrogen source. Now, Agapova et al. show that M. tuberculosis is not a picky eater. In the experiments, the bacteria were fed different nitrogen sources. Then, they tracked how well the bacteria grew. The experiments showed that M. tuberculosis happily eats many different amino acids and may use more than one as a nitrogen source at a time. It does not tightly control its stockpile of nitrogen sources the way other bacteria do, or use ammonium very efficiently. This suggests that M. tuberculosis has evolved to be very flexible in its dietary habits, which may explain why these bacteria can thrive in the varied environments within the human body. Knowing exactly how M. tuberculosis acquires and uses nitrogen may help scientists design ways to thwart the process and starve the bacteria.