A new target to fight tuberculosis
Oeiras, 21st May 2025
Tuberculosis is the world’s second deadliest infectious disease caused by a single microorganism, surpassed only by COVID-19 during the recent pandemic. Each year, more than 10 million fall ill and over 1.3 million people die from this disease. This situation is made worse by the rise of drug- and multidrug-resistant strains of Mycobacterium tuberculosis, the causative agent of the disease, highlighting the limits of current treatments and the urgent need for new therapies.
But what makes this bacteria so invincible? One major factor lies in its unique cell envelope, which acts as a shield to many antibiotics and our immune defenses. This is why it has attracted so much interest among researchers as a target for developing new therapies against tuberculosis.
In a recent study published in Nature Communications, an international team with ITQB NOVA researchers revealed the tridimensional structure of Arabinofuranosyltransferase (AftB), a protein involved in synthesizing components that maintain the integrity of M. tuberculosis’ cell envelope. Despite its importance, the structural and functional mechanisms of AftB have remained poorly understood until now.
Using cryo-electron microscopy (cryo-EM), a technique awarded the Nobel Prize in Chemistry in 2017, the team mapped the structure of this protein in detail. “We found that AftB has a distinctive irregular, tube-shaped cavity that allows two substrates, molecules it needs to do its job, to interact”, explains Margarida Archer, leader of the Membrane Protein Crystallography laboratory at ITQB NOVA and co-author of the paper. “This cavity could be targeted by competitive inhibitors that either directly inhibit AftB or enhance the effectiveness of existing antibiotics such as rifampicin”, she adds.
Inhibiting the synthesis of cell envelope components has already proven effective, one example being the front-line anti-tuberculosis drug ethambutol. “While future studies will be needed to fully explore the druggability of the AftB cavity, our comprehensive characterization of the protein’s structure and interactions lays the groundwork for future drug development”, advances José Rodrigues, ITQB NOVA researcher and co-author of the paper.
This work is part of an ongoing effort by an international consortium involving ITQB NOVA and coordinated by the Columbia University Irving Medical Center, which has been systematically uncovering the structure of arabinofuranosyltransferases in mycobacteria. Since 2020, the consortium has published three studies in leading journals, including Nature Communications, Molecular Cell and Processes.
Building on this line of research, the team is now “investigating mutations in AftB that may be linked to antibiotic resistance, as well as studying related enzymes, such as AftA and AftD, to better understand their mechanisms of action,” explains Margarida Archer. In parallel, the team is using computational strategies to identify drugs that are already commercialized that could be repurposed to fight tuberculosis.
By shedding light on one of the bacterium’s most vital mechanisms for resistance and pathogenicity, this research opens up promising new avenues to tackle one of the world’s deadliest infectious diseases.
The study was developed in collaboration with the University of Alberta (Canada); the University of Chicago, Columbia University Irving Medical Center, and Weill Cornell Medicine (USA); the University of Groningen (The Netherlands); Academia Sinica and the National Tsing Hua University (Taiwan); and the University of Warwick (UK).
