A New Weapon Against the “Number One Killer”: Discovering the Mechanism of Destroying Tuberculosis Bacteria from the Inside
After decades of decline in the developed world, tuberculosis (TB) is making a resurgence, with increasing resistance to the best antibiotics available. The World Health Organization (WHO) describes this situation as a “public health crisis,” but hope may soon be on the horizon in the fight against the world’s number one infectious killer.
An international team of researchers studied three promising experimental antibiotic compounds – ecumicin, ilamycins, and cyclomarins – to determine how they eliminate Mycobacterium tuberculosis, the bacteria that causes tuberculosis, according to a study published in the journal Nature Communications (Nature Communications).
Although these compounds and their potential as TB treatments are not new to scientists, questions remained about exactly how they inactivate TB bacteria. Understanding this mechanism is essential for developing large-scale treatments.
In laboratory tests, the researchers demonstrated that the three compounds act on a “molecular machine” inside the bacteria known as the ClpC1–ClpP1P2 complex. This complex is vital for TB bacteria, as it enables them to secure rid of unnecessary or damaged waste proteins.
“TB bacteria depend on this recycling system to survive, especially under stressful conditions inside the human body,” says immunologist Warwick Britton, from the University of Sydney in Australia.
Rising Tuberculosis Infections and Treatment Challenges
Recent reports reveal a worrying increase in tuberculosis infections, including among children in Europe. Tuberculosis is now surpassing COVID-19 as the infectious disease that kills the most humans globally. In 2024, an estimated 920,000 new TB cases and nearly 85,000 deaths occurred worldwide (WHO).
Britton added: “Our results show that these compounds do not simply shut down the system; rather, each of them intervenes in a different way, leading to widespread disruptions in the entire bacteria, and this disruption impairs their ability to function and survive.”
Analyzing Bacterial Protein Networks
The researchers analyzed more than 3,000 proteins in TB bacteria, testing each antibiotic compound individually to see how these proteins were affected. While all three compounds disrupted the bacteria’s protein recycling system, they did not all perform in the same way. The compound “ecumicin” had the greatest effect, causing a sharp rise in a protective protein called (Hsp20), a clear sign that the bacteria are under severe stress.
This means that the development of antibiotics containing these compounds can proceed with greater precision, with a much clearer picture of the damage they do to TB bacteria and how to combine them most effectively.
“By tracking changes across most of the bacterial protein network, we were able to see how disrupting a single essential complex can reshape the entire internal protein landscape of bacteria,” says chemical biologist Isabel Barter, from the University of Sydney. “This deeper understanding gives us valuable insight into how to improve these compounds and design more precise and effective treatments against TB.”
The Global Impact of Tuberculosis
Tuberculosis claims the lives of more than one million people annually and is transmitted through droplets in the air (through coughing or breathing). Although the disease is curable, effective treatments are not universally available, and a full course of treatment can take months, contributing to the emergence of antibiotic-resistant strains.
“Our study highlights the possibility of directly targeting this protein degradation system,” concludes chemical biologist Richard Payne, from the University of Sydney. “By understanding how different compounds interact with it and disrupt its normal functions, we can more strategically design the next generation of anti-TB drugs.”
The WHO estimates that in 2019, 819,000 people in the Eastern Mediterranean Region fell ill with TB, but only 6 in 10 received treatment (WHO). Continued research and collective action are crucial to ending the TB crisis, particularly in low- and middle-income countries (PMC).