Tuberculosis (TB) is the oldest and most deadly disease in human history, causing over 1.2 million deaths every year. TB is an infectious airborne disease that mainly affects the lungs. It is caused by the bacterium Mycobacterium tuberculosis (Mtb).
The main treatment option for TB is long courses of multiple antibiotics. However antimicrobial resistance (AMR) – a process in which bacteria have developed the ability to resist the action of medicines - has made it harder, longer and more costly to treat TB. Half a million people are infected with multidrug-resistant Mtb each year and the need for new treatment options is urgent.
Insufficient investment and innovation in TB drug development has led to a limited number of potential treatments reaching clinical trials.
To tackle the global health threat caused by TB, the IOI has awarded £5m to support the establishment of an Oxford consortium comprising chemists, biologists, clinicians, vaccinologists and health sociologists who will work collaboratively through 5 interconnected stages from drug discovery and testing to clinical trials and public engagement to develop new therapies for TB.
Tuberculosis is a perfect example of how we are returning to the pre-antibiotic era. Over 95% of TB patients used to be cured but now multidrug-resistant TB has become a leading cause of death due to AMR.
Sir Stewart Cole, Executive Chair of the IOI, said: ‘The IOI Grand Challenge award will bring together researchers with complementary skills to establish a successful pipeline for TB drug and therapeutic vaccine development spanning molecular epidemiology, medicinal chemistry, in vitro and in vivo evaluation, and clinical trials in regions most affected by this disease. TB and AMR cannot be solved in silos. The IOI Grand challenge award will facilitate collaborations across different disciplines and sectors to help solve this global health crisis.’
Prof Rachel Tanner, Associate Professor at the Jenner Institute within NDM and Lead Principal Investigator for the project, said: ‘The complex biology of the bacterium Mtb makes it inherently resistant to many potential drugs. There is a dearth of validated drug targets and investment towards new antibiotic discovery. The IOI Grand Challenge award will enable us to establish a cross-divisional collaborative and interdisciplinary research network with an integrated pipeline of therapeutic development to tackle the world’s most devastating pathogen.’
The five interconnected stages of the project are:
Stage 1: Medicinal chemistry to identify new compounds effective against Mtb
A team of chemists, biochemists and structural biologists led by IOI’s Dr Alistair Farley (co-PI) will apply a focussed medicinal chemistry approach to identify novel inhibitors and new approaches to TB chemotherapy at the early stage of the development pipeline.
Stage 2: In vitro and ex vivo evaluation
Led by Prof Rachel Tanner, compounds identified in stage 1 will be screened against a range of Mtb strains using Oxford’s existing in vitro/ex vivo models together with additional tools transferred from collaborators at Birkbeck, University of London and others.
Stage 3: Digital microbiology and computational science
Led by IOI’s Prof Sam Sheppard, epidemiology, genomics and phenotypic variation of Mtb will be applied to support therapeutic development.
Stage 4: In vivo evaluation
Oxford’s established expertise in Mtb murine challenge models will be applied to evaluate the most promising new TB drugs and drug/vaccine combinations. This will be led by Dr Elena Stylianou of the Nuffield Department of Medicine.
Stage 5: Preparation of the clinical pipeline
Prof Helen McShane of the Nuffield Department of Medicine will lead work to establish a clinical pipeline for TB drug testing, leveraging Oxford’s capacity in regions with the highest burden of TB. Public health and social science dimensions of developing a new treatment will also be considered, including public and patient involvement, ahead of potential clinical development.
Prof Helen McShane, Professor of Vaccinology at the Jenner Institute and co-Principal Investigator for the project, said: ‘Ensuring public trust and acceptance of new treatments is as important as developing the treatments themselves. We will start engaging with patient groups and health services staff at an early stage to ensure that their views and the issues most concerning to patients are taken into consideration.’
The TB Grand Challenge Award will begin in March 2025 and the project will run for three years.