Study explains molecular mechanisms of drug resistance in Mycobacterium tuberculosis

A group of researchers from France, Germany, Belarus, Japan, and Russia and headed by a scientist from Skolkovo Institute of Science and Technology (Skoltech) has discovered how Mycobacterium tuberculosis survives in iron-deficient environments by using rubredoxin B (RubB)—a protein that belongs to the rubredoxin family and plays a significant role in adapting to varying environmental conditions.

The new research work is part of an ongoing effort to investigate the function of M. tuberculosis enzymes in developing resistance to drugs and also to the human immune system. The study was published in the Bioorganic Chemistry journal.

According to the World Health Organization (WHO), tuberculosis infects 10 million people per year and kills about 1.5 million individuals, making it the leading infectious killer in the world. Mycobacterium tuberculosis—the bacterium responsible for causing tuberculosis—is known for its ability to live inside macrophages, which are immune system cells that kill harmful bacteria.

Over the last few decades, the continuous spread of M. tuberculosis drug resistance to extensively used therapeutics has become a significant clinical concern. In this context, the detection of new molecular drug targets and the interpretation of molecular mechanisms of drug resistance are highly significant.

Natallia Strushkevich, Assistant Professor from the Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE), and her collaborators investigated the crystal structure and function of RubB—a metalloprotein that plays a key role in the proper functioning of cytochrome P450 (CYP) proteins needed for bacterial pathogenicity and survival.

The researchers believe that when granulomas are formed, M. tuberculosis changes to a more iron-efficient RubB to survive iron-deficient conditions. But these are largely ineffective attempts at defense against tuberculosis by the immune system.

During the long-term co-evolution with mammals, M. tuberculosis developed a variety of strategies to subvert or evade the host innate immune response, from recognition of the bacterium and phagosomal defenses within infected macrophages, to adaptive immune responses by antigen presenting cells.”

Natallia Strushkevich, Assistant Professor, Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology

“Iron assimilation, storage and utilization is essential for M. tuberculosis pathogenesis and also involved in emergence of multi- and extensively-drug resistant strains. Heme is the preferable iron source for M. tuberculosis and serves as a cofactor for various metabolic enzymes. Based on our findings, we linked rubredoxin B to heme monoooxygenases important for metabolism of host immune oxysterols and antitubercular drugs,” added Strushkevich.

Our findings indicate that M. tuberculosis has its own xenobiotics transformation system resembling human drug-metabolizing system.”

Natallia Strushkevich, Assistant Professor, Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology

According to her, novel targets for drug design efforts are in high demand, and cytochrome P450 enzymes have evolved as novel targets for developing therapeutic agents for tuberculosis.

The traditional methods to inhibit these enzymes are not easy. Identifying an alternate redox partner, like RubB, allows a better understanding of their role in various host microenvironments. This understanding could be leveraged to find new ways to inhibit their function in M. tuberculosis.

The previous study made by the consortium demonstrated that one of the CYPs activated by RubB would work against SQ109, a potential drug candidate for multidrug-resistant tuberculosis. Yet another research work looked at how M. tuberculosis defends itself by intercepting human immune signaling molecules—a barrier that restricts the discovery of drugs.