Study uncovers molecular mechanisms of drug resistance in Mycobacterium tuberculosis

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• Source: Skolkovo Institute of Science and Technology (Skoltech)


• Date: 09 Apr,2021

A consortium of researchers from Russia, Belarus, Japan, Germany and France led by a Skoltech scientist have uncovered the way by which Mycobacterium tuberculosis survives in iron-deficient states by using rubredoxin B, a protein by a rubredoxin family that play an essential role in adaptation to changing environmental conditions.

The new study is part of an attempt to study the role of M. tuberculosis enzymes in creating immunity to the human immune system and medication. The paper was published in the journal Bioorganic Chemistry.

According to the World Health Organization, every year 10 million people fall ill with tuberculosis and about 1.5 million die from it, which makes it the world’s top infectious killer. The bacterium that causes TB, Mycobacterium tuberculosis, is notorious for its ability to survive within macrophages, cells of the immune system that destroy harmful bacteria.

Continuing spread of drug resistance of M. tuberculosis to widely used therapeutics over recent years became a significant clinical issue. In this respect, the identification of novel molecular drug targets and deciphering the molecular mechanisms of drug resistance are of critical importance.

Natallia Strushkevich, Assistant Professor at the Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE), and her colleagues analyzed the crystal structure and function of rubredoxin B (RubB), a metalloprotein that ensures the correct operation of cytochrome P450 (CYP) proteins essential to bacterial survival and pathogenicity.

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. 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.”

Natallia Strushkevich, Assistant Professor, Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE)

The team hypothesizes that M. tuberculosis switched to more iron-efficient RubB to endure iron starvation when granulomas are formed (these are largely unsuccessful efforts at defense against TB by the immune system).

Based on our finding, we linked rubredoxin B to heme monoooxygenases important for metabolism of host immune oxysterols and anti tubercular drugs. Our findings suggest that M. tuberculosis has its own xenobiotics transformation system resembling human drug metabolizing system,” explains Natallia Strushkevich.

The basic approaches to block these enzymes aren’t straightforward. Finding the alternative redox partner, such as RubB, enables further understanding of their function in various host microenvironments. This knowledge could be exploited to identify new strategies to block their function in M. tuberculosis.

Earlier research by the consortium showed that one of the CYPs enabled by RubB can act against SQ109, a promising drug candidate against multidrug-resistant tuberculosis. Another study focused on how Mycobacterium tuberculosis protects itself by intercepting human immune signaling molecules — a barrier that restricts drug discovery.