The study reveals the molecular mechanisms of drug resistance in Mycobacterium tuberculosis

A consortium of researchers from Russia, Belarus, Japan, Germany and France, led by scientist Skoltech, discovered how Mycobacterium tuberculosis survives iron deficiency using rubredoxin B, a protein from the rubredoxin family that plays an important role in adapting to changing environmental conditions.

The new study is part of an effort to study the role M. tuberculosis enzymes in the development of resistance to the human immune system and drugs. The paper was published in a journal Bioorganic chemistry.

According to the World Health Organization, every year 10 million people get tuberculosis and about 1.5 million die from it, making it the world’s top contagious killer. The bacterium that causes TB, Mycobacterium tuberculosis, is known for its ability to survive in macrophages, cells of the immune system that destroy harmful bacteria.

The continued spread of drug resistance to M. tuberculosis to widely used therapy over the last decades has become a significant clinical problem. In this regard, identifying new molecular targets of drugs and deciphering the molecular mechanisms of drug resistance are crucial.

Natallia Strushkevich, an assistant professor at the Skoltech Center for Computing and Science and Intensive Data Engineering (CDISE), and her colleagues studied the crystal structure and function of rubredoxin B (RubB), a metalloprotein that ensures the proper functioning of cytochrome P450 (CYP). ) proteins necessary for the survival and pathogenicity of bacteria.

The team hypothesizes that M. tuberculosis switched to RubB more efficiently than iron to survive iron starvation when granulomas form (these are mostly unsuccessful attempts by the immune system to defend TB).

During long-term coevolution with mammals, M. tuberculosis has developed a number of strategies to undermine or avoid the host’s innate immune response, from bacterial recognition and phagosomal defense within infected macrophages, to adaptive immune response by antigen-presenting cells. Assimilation, storage and use of iron is essential for the pathogenesis of M. tuberculosis, and is also involved in the emergence of strains resistant to more and more drugs. Heme is a preferred source of iron for M. tuberculosis and serves as a cofactor for various metabolic enzymes. “

Natallia Strushkevich, Assistant Professor, Skoltech Center for Computing and Informatics of Intensive Data (CDISE)

Based on our findings, we associated rubredoxin B with heme monooxygenases important for the metabolism of host immune oxysterols and antitubular drugs. Our findings indicate that M. tuberculosis has its own xenobiotic transformation system that resembles human drug metabolism, ”explains Natallia Strushkevich.

According to Natallia: New targets for drug design efforts are in high demand and cytochrome P450 enzymes have emerged as new targets for the development of therapeutic agents for tuberculosis.

Classical approaches to blocking these enzymes are not simple. Finding an alternative redox partner, such as RubB, allows for a further understanding of their function in different micro host environments. This knowledge could be used to discover new ways to block their function in M. tuberculosis.

Earlier research by the consortium has shown that one of the CYPs enabled by RubB can work against SQ109, a promising candidate for multidrug-resistant tuberculosis drugs. Another study focused on how Mycobacterium tuberculosis is protected by intercepting human immune signaling molecules – a barrier that limits drug detection.


Skolkovo Institute of Science and Technology (Skoltech)

Journal reference:

Sushko, T., and others. (2021) A new reversal of rubredoxin function in M. tuberculosis. Bioorganic chemistry.