The tuberculosis pathogen Mycobacterium tuberculosis comes first in the statistics of fatal infectious diseases. According to the World Health Organization (WHO), around 1.6 million people died of tuberculosis in 2018. It is still unclear why tuberculosis bacteria can resist the innate human immune system.
Defense against pathogens is the responsibility of certain white blood cells – the macrophages. Their job is to eat foreign proteins and microorganisms. While other pathogens perish inside the macrophages, tuberculosis pathogens can survive. Scientists assume that it is due to their diet.
New approach to medication
A cross-border research project has now succeeded in decoding the nutrition of the tuberculosis pathogens inside the macrophages. The findings also revealed a new promising approach to drug development.
They were involved research center Julich and the University of Surrey in Guildford (Great Britain).
Specifically, the researchers investigated where the vital nitrogen comes from, which the tuberculosis pathogen feeds on inside the macrophages.
Block tuberculosis pathogen production
They found that the tuberculosis pathogens feed on various amino acids in its host cells, the macrophages. The most important food source is glutamine. But glutamate, aspartate, alanine, glycine and valine also play a role. In contrast, the tuberculosis pathogen has no access to the macrophage’s serine. It also needs this nutrient to survive. However, I have to make it myself.
This aspect offered the researchers an approach for the development of new drugs: They want to paralyze the serine production of the tucerkulosis pathogen in order to combat it. Specifically, such an active ingredient could block phosphoserine transaminase, an enzyme that the pathogen relies on to produce serine.
Development of an own analysis method
The way to this finding was through the analysis of the nitrogen metabolism of the tuberculosis pathogen. The bacteria need certain building blocks for the production of the vital serine. One of the most important building blocks is nitrogen, which it obtains from the amino acids of the macrophage.
The researchers developed a special method for the analysis: they linked experimental investigations and computer simulations. In the experiments, they fed the infected macrophages with various amino acids. In each case, they replaced normal-weight nitrogen atoms – nitrogen isotopes with the mass number 14 (14N) – with heavier nitrogen atoms – mass number 15 (15N).
computer simulations
They later used mass spectrometry to determine the proportions and metabolites of the bacterium in which the 15N isotopes can be found. The British researchers were responsible for evaluating these experiments – and forming the basis for the computer simulations. These were in Institute for Bio and Earth Sciences in Research center Jülich developed. The computer model depicts the nitrogen metabolism, which determines the pathways of the amino acids that are taken up by the tuberculosis pathogen.
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