Researchers from Imperial and the London School of Hygiene & Tropical Medicine (LSHTM) have discovered a drug target that could potentially help tackle drug-resistant tuberculosis, one of the biggest causes of death worldwide.
Tuberculosis (TB) is one of the ten biggest causes of death worldwide, and one of the three biggest killers among infectious diseases. It caused over 1.25 million deaths in 2023.
"TB is still a major global problem. Millions are affected every year, disproportionately in low- and middle-income countries, and it's an under-recognised problem even in the UK," said Dr Gerald Larrouy-Maumus in Imperial's Department of Life Sciences, one of the study's co-authors. "To make progress, we need a new and radical approach."
Because the bacteria that cause it, Mycobacterium tuberculosis, are hard to reach with antibiotics, completely clearing an infection requires a long course of treatment with multiple antibiotics, and problems such as side-effects mean that patients often fail to follow this through to completion.
This creates a selective pressure for drug-resistant strains to evolve and subsequently spread within the patient and to other people. New drugs are therefore regularly needed to overcome antibiotic resistant strains of the bacteria.
The Imperial and LSHTM researchers, working in collaboration with pharmaceutical company Janssen Pharmaceutica (now Johnson & Johnson Innovative Medicine), discovered that inhibiting an enzyme found in the bacteria called PurF is effective at preventing the bacteria from replicating. This insight has potential to be used by medical researchers to develop new drugs that could get around existing drug-resistance by acting on a different target to existing treatments.
The team made the discovery, which they have published in Nature, after screening thousands of chemical compounds to find ones that kill M. tuberculosis. They found that a molecule known as JNJ-6640 stops the bacteria replicating. "There were a lot of hits but one we were quite excited about. We found one that's incredibly potent against TB," said Dr William Pearson at LSHTM, another study co-author.
Using techniques such as genetic analysis, protein studies and microscopy, the team revealed that compounds worked by inhibiting the PurF enzyme, which the bacteria use to synthesise molecules called purines that all cells need for functions such as metabolism and signalling.
While some bacteria can survive by taking purines from a human or animal host, the researchers used samples of lung tissue from humans and mice to show that the M. tuberculosis bacteria were unable to recover enough purines this way to survive. They then conducted in vivo trials using animal models, which found that JNJ-6640 is effective at reducing TB infection in mice.
While JNJ-6640 is not itself a suitable drug candidate because it is not stable enough when ingested, the discovery that inhibiting PurF is an effective way to defeat TB bacteria opens up a new strategy that researchers could use to look for new drug candidates.
Advanced resources
The research was funded by Janssen Pharmaceutica, the Bill and Melinda Gates Foundation and Wellcome. It was also supported by the Agilent Measurement Suite, an analytical science facility at Imperial's White City Campus that provides researchers from Imperial and with access to advanced equipment and technical support.
"The metabolomics using the Agilent instrumentation allowed us to see in chemical terms the products of the PurF enzyme decrease in response to the test compound. This helped us to identify what part of the bacteria were targeted," said co-author Dr Richard Wall at LSHTM. "The open access to state-of-the-art equipment and tailored analysis provided by the Suite was invaluable."
Next steps
Efforts are now ongoing to optimise compounds against this novel drug target, and the published research is available to drug development experts around the world.
Targeting de novo purine biosynthesis for tuberculosis treatment is published in Nature 644, 214–220.
