More Medicines for Tuberculosis
Lead Research Organisation:
John Innes Centre
Department Name: UNLISTED
Abstract
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Technical Summary
The More Medicines for Tuberculosis (MM4TB - EU FP7) consortium has evolved from the highly successful FP6 project, New Medicines for TB (NM4TB), which delivered a candidate drug for clinical development. Building on these foundations, MM4TB will continue to develop new drugs for TB treatment. An integrated approach will be implemented by a multidisciplinary team that combines some of Europe's leading academic TB researchers with two major pharmaceutical companies and four SMEs, all strongly committed to the discovery of anti-infective agents. MM4TB will use a tripartite screening strategy to discover new hits in libraries of natural products and synthetic compounds, while concentrating on both classical and innovative targets that have been pharmacologically validated. Whole cell screens will be conducted against Mycobacterium tuberculosis using in vitro and ex vivo models for active growth, latency and intracellular infection. Hits that are positive in two or more of these models will then be used for target identification. Targets thus selected will enter assay development, structure determination, fragment-based and rational drug design programs; functionally related targets will be found using metabolic pathway reconstruction. The role of JIC (AM lab) will be to develop M. tuberculosis gyrase as a target and establishing the mechanism of action of novel compounds that target this enzyme. This will involve biochemistry and structural methods (X-ray crystallography), carried out in collaboration with the Lawson laboratory. Medicinal chemistry, carried out in other labs in the consortium, will convert leads to molecules with drug-like properties for evaluation of efficacy in different animal models and late preclinical testing.
Planned Impact
unavailable
People |
ORCID iD |
| Anthony Maxwell (Principal Investigator) |
Publications
Djaout K
(2016)
Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis.
in Scientific reports
Mori G
(2018)
The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase.
in Tuberculosis (Edinburgh, Scotland)
Nagaraja V
(2017)
DNA topoisomerase I and DNA gyrase as targets for TB therapy.
in Drug discovery today
Sipos A
(2015)
Lead selection and characterization of antitubercular compounds using the Nested Chemical Library.
in Tuberculosis (Edinburgh, Scotland)
| Description | We have evaluated about 300,000 compounds for their potential as anti-TB compounds. Some of these will be considered as new TB drugs. |
| Exploitation Route | Others may pick up these findings and use the data in drug-development programmes |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| URL | http://www.mm4tb.org/ |
| Description | Nagaraja |
| Organisation | Indian Institute of Science Bangalore |
| Country | India |
| Sector | Academic/University |
| PI Contribution | Collaborative experiments and provision of materials. Detailed discussions on projects |
| Collaborator Contribution | Collaborative experiments and provision of materials. Detailed discussions on projects |
| Impact | Several research papers: 1. M. Chatterji, S. Unniram, A. Maxwell, V. Nagaraja, The additional 165 amino acids in the B protein of Escherichia coli DNA gyrase have an important role in DNA binding. J. Biol. Chem. 275, 22888-22894 (2000). 2. M. Chatterji, S. Unniraman, A. Maxwell, V. Nagaraja, The additional 165 amino acids in the B protein of Escherichia coli DNA gyrase have an important role in DNA binding. J Biol Chem 275, 22888-22894 (2000). 3. U. H. Manjunatha, A. Maxwell, V. Nagaraja, A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism. Nucleic Acids Res 33, 3085-3094 (2005). 4. U. H. Manjunatha, A. Maxwell, V. Nagaraja, A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism. Nucleic Acids Res 33, 3085-3094 (2005). 5. G. Mori et al., The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase. Tuberculosis 112, 98-109 (2018). 6. V. Nagaraja, A. A. Godbole, S. R. Henderson, A. Maxwell, DNA topoisomerase I and DNA gyrase as targets for TB therapy. Drug Discov Today 22, 510-518 (2017). 7. A. Sipos et al., Lead selection and characterization of antitubercular compounds using the Nested Chemical Library. Tuberculosis 95 Suppl 1, S200-206 (2015). |
| Description | mm4tb |
| Organisation | Swiss Federal Institute of Technology in Lausanne (EPFL) |
| Country | Switzerland |
| Sector | Public |
| PI Contribution | We were one of ~25 labs on the EU-funded More Medicines for Tuberculosis consortium. Our role was to provide expertise etc on M. tuberculosis gyrase to evaluate compounds provided by other consortium members. |
| Collaborator Contribution | Principally to provide new compounds for evaluation |
| Impact | 4 papers: 1. K. Djaout et al., Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis. Scientific reports 6, 27792 (2016). 2. G. Mori et al., The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase. Tuberculosis 112, 98-109 (2018). 3. V. Nagaraja, A. A. Godbole, S. R. Henderson, A. Maxwell, DNA topoisomerase I and DNA gyrase as targets for TB therapy. Drug Discov Today 22, 510-518 (2017). 4. A. Sipos et al., Lead selection and characterization of antitubercular compounds using the Nested Chemical Library. Tuberculosis 95 Suppl 1, S200-206 (2015). Multidisciplinary |
| Start Year | 2011 |
| Description | London International Youth Forum |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Undergraduate students |
| Results and Impact | • Aug 2017 - lecture to students visiting as part of London International Youth Science Form: 'Where will the new antibiotics come from?' |
| Year(s) Of Engagement Activity | 2017 |