Researchers from the Institut Pasteur de Montevideo, in collaboration with Argentinian scientists, managed to understand the workings of a protein from the bacterium that causes tuberculosis, which is key to regulating the virulence of the pathogen. The findings —published in Nature Communications on July 24— provide valuable tools to fight the disease, because this protein may be a target for new anti-tuberculosis drugs.
The protein studied is called FasR (an acronym for Fatty Acid Synthase Regulator) and its function is to perceive, as if it were an antenna, the changes in the amount of fatty acids inside the bacterium Mycobacterium tuberculosis, which causes a disease that results in over 1 million deaths per year.
The study allowed, first, to understand how FasR detects long-chain fatty acids, which in the bacterium are fundamental constituents of the external wall, conferring particular resistance. Second, it uncovered how FasR binds to the DNA of the bacterium, ultimately controling the production of the fatty acid synthesis machinery.
These contributions were possible because the researchers were able to actually see the protein, with atomic detail (“atom by atom”) using X-ray crystallography. The researchers were able to observe FasR in the presence and absence of fatty acids, as well as attached to DNA, revealing fascinating movements that explain FasR’s function.
This work is relevant not only because it paves the way to designing new antibiotics against tuberculosis, but also because it shows that all FasR-like proteins have a common mechanism. This family of proteins is very large in many bacteria, being able to respond to a huge diversity of signals and regulating many essential cellular processes. Therefore, many of its members are therapeutic targets that are already being considered for combating a number of pathogens.
The team of researchers was led by Alejandro Buschiazzo, head of the Laboratory of Molecular and Structural Microbiology at the IP Montevideo, and Hugo Gramajo, of the Laboratory of Physiology and Genetics of Actinomycetes at the Institute of Molecular and Cellular Biology of Rosario (IBR-CONICET) Universidad Nacional de Rosario, Argentina. Felipe Trajtenberg and Nicole Larrieux in the IP Montevideo team, also participated.
Lara, J., Diacovich, L., Trajtenberg, F. et al. Mycobacterium tuberculosis FasR senses long fatty acyl-CoA through a tunnel and a hydrophobic transmission spine. Nat Commun 11, 3703 (2020). https://doi.org/10.1038/s41467-020-17504-x