HMN 2026: How Ordinary enzyme that evolves into ‘control switch’ reveals tuberculosis weak spot

Researchers at the University of Surrey have identified a protein that acts as a control switch, preventing Mycobacterium tuberculosis from accessing the energy sources it needs to survive. The discovery points to a specific vulnerability in the bacterium that could be targeted by new tuberculosis (TB) treatments. The work is published in the journal EMBO Reports.

TB remains a major global health threat. It is estimated that around 25% of the world’s population carries latent TB infection, and in 2023 alone there were more than 11 million active TB cases and 1.3 million deaths. A key to Mycobacterium tuberculosis’s success is its remarkable metabolic flexibility, which allows it to use a wide range of nutrients found inside the human body.

This large study, which involved scientists at Surrey, Imperial College London, the University of Birmingham, the Indian Institute of Science and the University of California, Irvine, discovered a unique regulatory protein that acts as a molecular “control switch,” enabling M. tuberculosis to access crucial energy sources it needs to survive in the host and cause disease.

Dr. Jane Newcombe, a research fellow at the University of Surrey and lead author of the paper, said, “TB continues to be a largely uncontrolled pandemic that disproportionately impacts society’s most marginalized populations. Sadly, it receives only a fraction of the funding and resources allocated to diseases that affect individuals across all socioeconomic levels equally, and as a result, our basic understanding of this pathogen still lags behind.”

Using biochemical and systems-level analyses, the team identified an enzyme they named virulence associated dikinase (VadK). VadK plays a critical role in the metabolism of nutrients, including those essential for bacterial survival in the host, and is required for the bacterium to cause tuberculosis.

Co-author Dr. Tom Mendum from the University of Surrey, who proposed the name VadK, explained, “Our work shows that this enzyme has effectively changed its job. VadK has evolved from a metabolic enzyme called pyruvate phosphate dikinase into a specialized regulator that helps the TB bacterium thrive during infection.”

By constructing evolutionary trees, the researchers also found that VadK-like enzymes appear to have evolved independently multiple times in other bacterial pathogens. This suggests that VadK—or related proteins—may contribute more broadly to bacterial virulence and could represent a common weak spot that future antibiotics might target.

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