Scientists identify ‘Achilles heel’ of world’s deadliest infectious disease

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MANILA, Philippines – Long before COVID-19 reshaped global health systems, tuberculosis (TB) was already the planet’s most lethal infectious disease. The ancient respiratory illness — traced as far back as 9,000 years — devastated Europe in the 18th and 19th centuries and continues to kill millions despite being both treatable and curable.

Today, TB is far from a relic. Even in high-income countries where it was thought to be eliminated, cases are rising again. The US has seen resurgences in California, Kansas, Maine, North Carolina, and New York — a trend partly fueled by the COVID-19 pandemic, when patients avoided clinics and delayed diagnosis out of fear of the coronavirus.

But new research suggests the bacterium Mycobacterium tuberculosis may have a critical vulnerability — one scientists could exploit for a new generation of treatments.

A molecular ‘heart and lungs’

A team led by infectious disease microbiologist Shelley Haydel of Arizona State University has identified a system inside the bacterium that it “cannot live without.”

This system, called PrrAB, acts like the microbe’s core life-support mechanism: it regulates genes needed for respiration and energy production. When the system is switched off, TB dies.

Using CRISPR interference (CRISPRi) — a tool that represses specific genes — the researchers silenced PrrAB in TB bacteria grown in the lab. The result: the bacterial population collapsed, dropping nearly a hundredfold.

“The essentiality of the PrrAB two-component system in Mycobacterium tuberculosis positions it as a promising therapeutic target,” Haydel wrote in the study published in ACS Infectious Diseases.

While not all mycobacterial species reacted the same way in the lab, PrrAB proved indispensable for the TB pathogen.

A compound that hits TB where it hurts

The team also found that an experimental compound known as DAT-48 — previously studied for its anti-TB potential — kills the bacteria by inhibiting the PrrAB pathway.

When combined with CRISPRi-mediated repression, DAT-48 became even more lethal to the bacterium. Even without CRISPRi, the compound showed synergy with existing TB drugs, including bedaquiline and telacebec, suggesting that disrupting PrrAB may weaken the bacterium’s defenses.

“DAT-48 exhibited potent activity against M. tuberculosis and synergy with respiratory inhibitors,” Haydel said. “These results highlight PrrAB as a central regulatory hub.”

A step toward eradicating the infectious disease?

The findings remain at the in vitro stage — meaning they have not yet been tested in animals or humans. But if future studies confirm the same vulnerability inside the human body, the discovery could open the door to therapies that explicitly target TB’s life-support system.

Such breakthroughs are urgently needed. Despite decades of medical advances, TB still kills more people worldwide than any other infectious disease, according to the US Centers for Disease Control and Prevention.

If PrrAB-targeting treatments like DAT-48 prove safe and effective, scientists say TB could one day follow smallpox into global eradication.

For now, the world waits for the next stage of research — and for the possibility that one of humanity’s oldest killers finally meets its match.