Lansoprazole sulphide bound in the active site of the respiratory chain supercomplex from M. smegmatis. Image: Terezia Kovalova/Stockholm University

“Lansoprazole, an acid reflux drug, and its metabolite lansoprazole sulphide, has shown potential as an anti-TB compound in tests using live cells infected with tuberculosis, TB. There have been speculations that it targets the respiratory chain proteins, but the mechanism of inhibition has remained undescribed”, says Terezia Kovalova, Department of Biochemistry and Biophysics, Stockholm University, first author of the study.

With the use of modern multidisciplinary approaches that included computational, biochemical, and structural biology-related methods, a team of researchers from the Department of Biochemistry and Biophysics at Stockholm University tested and described the inhibitory influence of lansoprazole sulphide on the activity of the respiratory chain protein of Mycobacterium smegmatis. It is a non-pathogenic bacterium closely related to TB and the studied protein complex is almost identical to the one from TB and thus presents an optimal research target.

“We analysed the binding site and the contacts the lansoprazole sulphide molecule makes with individual amino acids of the respiratory chain protein, which is the direct cause of the inhibition of the complexes’ activity, in detail. This can be used as a ground work for further drug development using this target”, says Terezia Kovalova.

Drug resistant TB a growing threat

Resistance to known and commonly used drugs can lead to normally easy-to-cure illnesses becoming life-threatening. An even more dangerous situation arises when an already fatal disease becomes resistant to known treatment. One of the most commonly spread diseases is tuberculosis (TB). According to the World Health Organization (WHO), TB, with its 1.25 million deaths in 2023, is the leading cause of death from a single infectious agent worldwide. It is currently present in all countries and endangers all age groups.

The treatment of non-resistant TB consists of 4 to 6 months of continuous treatment with multiple antibiotics. Infection with resistant TB is more challenging as the chemicals used to treat it are more expensive and toxic to patients.

Discovering and developing new drugs takes on average around 12 years and costs hundreds of millions of dollars. To cut the time and cost of the process, many already approved and used drugs are being retested to see if they can be potentially repurposed against different illnesses or conditions. One of these is Lansoprazole.

Cellular respiration promising target for new drugs

Cellular respiration is the process in which cells convert chemical energy acquired through nutrition into energy to power all the processes necessary for survival of the cell, or in this case the bacterium. Therefore, the proteins involved in this process are promising as targets for new drugs. The genetic differences between human respiratory proteins and one from TB translate into changes in their 3D structure, which leads to different abilities for certain chemicals to interact with them. A detailed understanding of these interactions helps to develop and enhance compounds that can stop the proteins of the targeted organism but not interact with the human versions of the same proteins.

Find the study “Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide” in PNAS (Proceedings of the National Academy of Sciences). DOI: https://doi.org/10.1073/pnas.2412780121