New study explains Mycobacterium tuberculosis high resistance to drugs and immunity

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Graphical summary. Credit: Bioorganic Chemistry (2021). DOI: 10.1016/j.bioorg.2021.104721

A consortium of researchers from Russia, Belarus, Japan, Germany and France led by a Skoltech scientist have uncovered the best way by which Mycobacterium tuberculosis survives in iron-deficient circumstances by using rubredoxin B, a protein from a rubredoxin household that play an vital function in adaptation to altering environmental circumstances. The new study is a part of an effort to study the function of M. tuberculosis enzymes in growing resistance to the human immune system and remedy. The paper was revealed within the journal Bioorganic Chemistry.

According to the World Health Organization, yearly 10 million individuals fall ailing with tuberculosis and about 1.5 million die from it, making it the world’s prime infectious killer. The bacterium that causes TB, Mycobacterium tuberculosis, is infamous for its capability to survive inside macrophages, cells of the immune system that destroy dangerous micro organism. Continuing unfold of drug resistance of M. tuberculosis to broadly used therapeutics over latest many years turned a considerable scientific drawback. In this regard, the identification of novel molecular drug targets and deciphering the molecular mechanisms of drug resistance are of pivotal significance.

Natallia Strushkevich, Assistant Professor on the Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE), and her colleagues studied the crystal construction and perform of rubredoxin B (RubB), a metalloprotein that ensures the right functioning of cytochrome P450 (CYP) proteins important to bacterial survival and pathogenicity. The workforce hypothesizes that M. tuberculosis converted to extra iron-efficient RubB to survive iron hunger when granulomas are shaped (these are largely unsuccessful makes an attempt at protection in opposition to TB by the immune system).

“During the long-term co-evolution with mammals, M. tuberculosis developed quite a lot of methods to subvert or evade the host innate immune response, from recognition of the bacterium and phagosomal defenses inside contaminated 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. Based on our finding, we linked rubredoxin B to heme monoooxygenases important for metabolism of host immune oxysterols and anti tubercular drugs. Our findings indicate that M. tuberculosis has its own xenobiotics transformation system resembling human drug metabolizing system,” explains Natallia Strushkevich.

According to Natallia: New targets for drug design efforts are in nice demand and the cytochrome P450 enzymes have emerged as novel targets for the event of tuberculosis therapeutic brokers. The traditional approaches to block these enzymes are usually not easy. Finding the choice redox accomplice, similar to RubB, permits additional understanding of their perform in several host microenvironments. This information may very well be exploited to establish new methods to block their perform in M. tuberculosis.

Earlier analysis by the consortium confirmed that one of many CYPs enabled by RubB can act in opposition to SQ109, a promising drug candidate in opposition to multidrug-resistant tuberculosis. Another study targeted on how Mycobacterium tuberculosis protects itself by intercepting human immune signaling molecules—a hurdle that limits drug discovery.


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More info:
Tatsiana Sushko et al. A brand new twist of rubredoxin perform in M. tuberculosis, Bioorganic Chemistry (2021). DOI: 10.1016/j.bioorg.2021.104721

Provided by
Skolkovo Institute of Science and Technology


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New study explains Mycobacterium tuberculosis high resistance to drugs and immunity (2021, April 8)
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