British scientists say they have found how a key drug can kill the tuberculosis bacterium, potentially paving the way for the development of new therapies.
A study led by scientists at the University of Birmingham, UK, examined how ethambutol, which has been one of the main drugs against TB since its discovery in 1961, kills bacterium.
The researchers confirmed that Emb proteins are targeted by ethambutol. Although the importance of these proteins had previously been recognised, a lack of structural and biochemical data had prevented scientists from confirming precisely how the drug targets them.
Writing in Science, the research team, which also comprised scientists from ShanghaiTech, in China, and the University of Queensland in Australia, describe using cryogenic electron microscopy and x-ray imaging to study the structures of a series of Emb proteins for the first time.
They showed how different Emb proteins were responsible for specific physiological functions producing crucial components of the TB cell wall, and also demonstrated how ethambutol binds to and inactivates these Emb proteins.
One of the lead study authors, Professor Gurdyal Besra, in the university’s Institute of Microbiology and Infection and the School of Biosciences, said: “This exciting breakthrough with our colleagues from China and Australia will inform a range of medical researchers from a wide range of disciplines; from structural biologists, biochemists, chemists, and microbiologists, and most importantly, scientists in the pharmaceutical industry aiming to develop new TB antibiotics targeting this unique set of proteins for the first time".
Zhang et al. Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol. Science 23 April 2020.
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