Demuris Ltd, in collaboration with UK and US scientists, have identified an antibiotic that may have potential in treating the 600,000 cases per year of Multi-Drug-Resistant Tuberculosis (MDR-TB).
The World Health Organisation (WHO) estimates that someone dies from TB every 20 seconds, or around 1.7 million people per year. Mycobacterium tuberculosis is the causative agent of tuberculosis (TB) and we have demonstrated that our antibiotic not only inhibits the growth of M. tuberculosis but also strains which are resistant to rifampicin, which is the first line therapy for the treatment of TB.
In the journal Molecular Cell (DOI: https://doi.org/10.1016/j.molcel.2018.08.028) we report the screening and identification of this compound along with its mechanism of action.
Through screening a relatively small number of extracts (only 2,000) from the Demuris Actinomycete Collection we identified the natural product antibiotic kanglemycin A. This compound is produced by an actinomycete bacterium and is similar to rifampicin but has several additional features which give it superior activity.
Biochemical and X-ray crystallography methods enabled us to understand how this compound works. It binds to the essential bacterial enzyme RNA polymerase, but crucially not the human version. It bypasses the normal rifampicin resistance mechanisms by making additional interactions with the RNA polymerase not seen before. It is these interactions that allow it to be active against the mutated and usually resistant version of the RNA polymerase in MDR-TB.
The work at Demuris was funded by Innovate UK and without this support from the UK government this project could not have gone ahead.
We have patented this compound and we are now looking to develop new versions which we expect to be even more active against MDR-TB.
The research project involved a large multidisciplinary team involving Newcastle and Penn State University scientists, Public Health England, Newcastle upon Tyne Hospitals NHS Foundation Trust and Demuris Ltd.
Professor Jeff Errington, CEO at Demuris, said: “This exciting project validates our company strategy of using state of the art genetic and biochemical assays and a uniquely diverse and well dereplicated collection of actinobacteria to discover new antibiotics. We have also benefitted by having access to a world class group of academic scientists covering the microbiology, biochemistry and structural biology methods needed for the project. This is the first of a string of new drug starting points coming from the Demuris portfolio”.
Dr Nick Allenby, Principal Scientist at Demuris, said: “There is an urgent need for new antibiotics to combat drug resistant Mycobacterium tuberculosis.
“We have shown that our compound discovered through a collaboration with Newcastle University is effective against these drug resistant strains.
“However, before we can start to think about using the compound much more work and development is needed. The next step for our compound is to prove that it is safe and effective for use in the clinic.”
Professor Nikolay Zenkin, from Newcastle University’s Institute for Cell and Molecular Biosciences said: “Treatment of TB involves a cocktail of antibiotics administered over many months, and resistance to several key antibiotics is becoming a major public health problem around the world.
“Our findings are very exciting and the first step towards developing a new, effective drug treatment for patients with rifampicin resistant TB to prevent fatalities in the future.”
Dr Michael Hall, from Newcastle University, who led chemical characterization of kanglemycin A, added: “This is an exciting development for the future treatment of rifampicin resistant TB and shows what can be achieved when local businesses and universities work together.”