Characterizing the structure, function and drugability of tuberculosis proteins using Rv1127c as a paradigm
Lead Research Organisation:
University of Surrey
Department Name: Microbial & Cellular Sciences
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
| Description | We have discovered a unique regulatory protein that is required for M. tuberculosis to consume energy sources essential for its survival in the host and for its ability to cause disease. We have shown that without this protein M. tuberculosis cannot grow in human cells or cause tuberculosis disease in a mouse. We have shown that this regulatory protein that we have named Virulence Associated Dikinase (VadK), coordinates metabolism and virulence by interacting with protein partners. |
| Exploitation Route | We have filed a patent based on the compounds developed during this partnering award. These compounds can be exploited by drug developers. |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| Description | Development of antibiotic adjuvants as a cheap non toxic approach to treat tuberculosis |
| Amount | £457,000 (GBP) |
| Funding ID | MR/X502698/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2025 |
| End | 11/2025 |
| Description | Development of lead compounds targeted to Mycobacterium tuberculosis |
| Amount | £86,024 (GBP) |
| Organisation | University of Surrey |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 06/2022 |
| End | 09/2023 |
| Title | Potential New Drugs for Treating Tuberculosis |
| Description | The inventors conducted a screening of 8,892 regulatory agency-approved drugs and molecules that have progressed to Phase II clinical trials. They employed ligand-based virtual screening using a homology model of Rv1127c as a novel drug target for TB. The top 25 hits were computationally validated through 100 ns molecular dynamic 5 simulations of docked complexes. This method identified several compounds, including those from the oxicam family of non-steroidal anti-inflammatory drugs (NSAIDs). The inventors tested these compounds for Rv1127c-specific anti-TB activity and surprisingly found that droxicam exhibited the most promising results. Further experiments demonstrated that droxicam effectively inhibited the growth of 10 Mycobacterium inside host macrophage cells without causing toxicity to mammalian cells. Building upon this work, the inventors then set out to explore the role of oxicam compounds as chemical tools in studying the role of Rv1127c in Mycobacterium metabolism and pathogenesis, as well as the druggability of Rv1127c as a novel target. In the course of medicinal chemistry optimization, 18 novel oxicam compounds 15 were synthesised, with surprisingly improved MICs and superior drug-like properties that synergize with existing TB treatments (Figures 1 and 2). Additionally, the inventors have demonstrated that these compounds exhibit selective toxicity against mycobacteria while remaining non-toxic to eukaryotic cells (Figure 3). Moreover, the inventors have demonstrated the efficacy ex vivo of these compounds within 20 macrophages (Figure 3), indicating their potential to eliminate both intracellular and extracellular TB. |
| IP Reference | |
| Protection | Patent / Patent application |
| Year Protection Granted | 2024 |
| Licensed | No |
| Description | Compton Fete stall |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | This was our annual bacterial stall at the Compton fete. We are now regulars and update our child friendly activities each year. This year we introduced a stall that focused on the "good bacteria" introducing the concept of the microbiome. |
| Year(s) Of Engagement Activity | 2024 |
| Description | Pint of Science |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Pint of Science: "The most unromantic way to die in the 21st Century" Public outreach event at Zero Carbon in Guildford. Very successful interactive session engaging the public by comparing the Covid-19 pandemic to the TB pandemic. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Pint of Science |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | An interactive session on antibiotic resistance which included the history of antibiotics and phage therapies. We also included some of our research on tuberculosis. |
| Year(s) Of Engagement Activity | 2023 |
| Description | Pint of Science |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | There is a disease that has been studied for 142 years responsible for a pandemic that once again kills more people than any other infection, including one third of the deaths due to antibiotic resistance. It is caused by an extraordinary bacterium that can either be totally silent and symptomless or turn your lungs to the consistency of cheese and, if untreated, poorly treated, or antibiotic resistant, a protracted and debilitating illness that ultimately leads to a horrendous death by suffocation. Come and find out about our efforts to understand so that we can kill this formidable pathogen. This was an interactive session debunking ideas about tuberculosis, introducing basic concepts in antibiotics and resistance and showcasing the research from our UKRI funded grants. |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://pintofscience.com/ |
| Description | Podcast on Tuberculosis |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Podcast on tuberculosis: The forgotten pandemic Tuberculosis Genomics • • https://soundcloud.com/microbinfie/64-mycobacterium-tuberculosis-the-forgotten-pandemic • https://open.spotify.com/episode/0GQ6BEvntjwhQmwNdXeCDS?si=adb169a9def74827 • https://podcasts.apple.com/au/podcast/64-mycobacterium-tuberculosis-the-forgotten-pandemic/id1479852809?i=1000538531466 Episode 65 links: • https://open.spotify.com/episode/1zilnX4TA4VbC0LqELVbWU?si=ff3815a1cf2c4949 • https://soundcloud.com/microbinfie/65-genomics-of-mycobacterium-tuberculosis • https://podcasts.apple.com/au/podcast/65-genomics-of-mycobacterium-tuberculosis/id1479852809?i=1000539961245 531466 |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://open.spotify.com/episode/0GQ6BEvntjwhQmwNdXeCDS?si=adb169a9def74827 |
| Description | Stand at the Compton Fair |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Compton Fair: Superbugs and Superfriends Successful stall for kids and adults with spin the wheel, antibiotic skittles, find your bacterial twin, microscopy and more Very popular as evidenced by the high footfall and was asked to run again in 2023 and recruited for the Farnham fair. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Stand at the Compton Fair |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | A stall att he Compton fair which included interactive activities aimed at different age groups. |
| Year(s) Of Engagement Activity | 2023 |