ATP-dependent Mur ligases in Mycobacterium tuberculosis: search for potential therapeutic targets against Tuberculosis.

Lead Research Organisation: Birkbeck College
Department Name: Biological Sciences

Abstract

Tuberculosis (TB) a contagious disease caused by the ?Superbug? Mycobacterium tuberculosis, remains the leading cause of death worldwide.

Despite the presence of chemotherapy, extensive rise in antibiotic resistance is a cause of concern around the world, including the UK. In a reported case of extreme drug resistance (XDR) there is no new drug available that can combat the disease. Hence there is an urgent need for new drug development.

A key feature of Mycobacterium tuberculosis is the unique cell wall of consisting of three major layers - peptidoglycan, arabinogalactan and mycolic acid covalently linked. The cell wall architecture and presence of ?peptidoglycans?, not only helps in maintaining the shape and size of the bacterial cell, but also protects the bacteria from toxic radicals, osmotic lysis, and foreign attack.

Thus the crucial nature of the protective cell wall-peptidoglycan in M. tuberculosis should be exploited for new drug discovery against TB. Characterisation of the peptidoglycan biosynthesis will help in identification of potential targets for new drugs.

The proposed study aims to identify those cellular components (enzymes) that are vital to the production of this protective cell wall, and thus essential for the survival of the TB-bacteria. We will be investigating, in detail, the structural and functional dynamics of the enzymes that play major roles in the peptidoglycan biosynthesis. In addition, we will also modify these vitally important TB enzymes and observe how the TB-Superbugs survive.

Technical Summary

The recurrence of Tuberculosis (TB) as a global health emergency has highlighted the urgent need for new therapeutic targets to facilitate the development of new drugs against the disease. TB is caused by the micro-organism Mycobacterium tuberculosis which is a member of the order Actinomycetales. A key common feature of this order is their complex cell walls, which consist of an unusual mycolyl-arabinogalactan-peptidoglycan (mAGP) complex. Within the cell wall, peptidoglycan not only provides shape and structural integrity to the bacterial cell, but also plays a critical role in protecting the bacteria against osmotic lysis and hydrolytic enzymes produced by host defence mechanisms. Mycobacterium tuberculosis is unique in its peptidoglycan architecture indicating that the enzymes regulating the synthesis of the pivotal substrates are novel therapeutic targets.

UDP-N-acetylmuramoyl-tripeptide ligase (MurE) is a member of the ATP-dependent ligase family and incorporates different amino acids including meso-diaminopimelate into peptidoglycan during synthesis in a species-specific manner. In addition, MurF acts at the final stage of UDP sugar linked polypeptide synthesis. The product of this reaction, UDP N-acetyl muramoyl pentapeptide, is the key substrate for the membrane bound transition stage of peptidoglycan biosynthesis. Due to the multi-facetted nature of the functional implications of ATP-dependent ligases, it provides a possible vulnerability that can be exploited. MurE and MurF are coded for in the M. tuberculosis genome by a single copy of the gene. This decreases the possibility that any disruption of the MurE and/or MurF protein will be compensated for by an alternative biochemical pathway. Moreover, these enzymes do not have human homologues. The combinations of these features make ATP-dependent ligases excellent candidates for the identification of novel therapeutic drug targets.

These two biochemical steps are pivotal for endogenous peptidoglycan biosynthesis pathways. Our knowledge is limited in these central biochemical reactions of Mycobacterium tuberculosis, the enzymes involved in these reaction steps and their regulation, on the cell function and physiology of the unique genus. We propose to elucidate the structure and function of the enzymes involved in the series of functionally linked ATP dependant ligation reactions in Mycobacterium tuberculosis, which are potential drug targets for combating TB.

Publications

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Diaz LE (2012) Antioxidant, antitubercular and cytotoxic activities of Piper imperiale. in Molecules (Basel, Switzerland)

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Evangelopoulos D (2010) Rapid methods for testing inhibitors of mycobacterial growth. in Methods in molecular biology (Clifton, N.J.)

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Evangelopoulos D (2014) Characterisation of a putative AraC transcriptional regulator from Mycobacterium smegmatis. in Tuberculosis (Edinburgh, Scotland)

 
Title A short film launched to commemorate World TB Day 
Description a short film was produced and launched at the World TB Summit in London to commemorate the World TB Day in 2014 
Type Of Art Film/Video/Animation 
Year Produced 2014 
Impact enhanced public engagement and understanding in TB control, education and laboratory research. 
URL http://www.youtube.com/watch?v=gvvvTM__GFI
 
Description Citation in Future Science
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
URL http://www.future-science.com/doi/full/10.4155/fmc.11.119
 
Description Engaging local MP and a Member of House of Lords in TB control
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description Mentoring Session at INTERNATIONAL UNION on Antibitic Resistance in TB
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.stoptb.org/assets/documents/
 
Description Birkbeck Commercial Development Fund (Seed Fund)/ Birkbeck University of London
Amount £6,000 (GBP)
Organisation Birkbeck, University of London 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2011 
End 12/2012
 
Description Birkbeck Translational Research Awards/Birkbeck University of London
Amount £10,000 (GBP)
Organisation Birkbeck, University of London 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 12/2012
 
Description Bloomsbury Graduate Scholarship
Amount £60,000 (GBP)
Organisation Birkbeck, University of London 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2009 
End 09/2012
 
Description European Respiratory Society Short-term Research Fellowship
Amount £10,000 (GBP)
Organisation European Respiratory Society (ERS) 
Sector Charity/Non Profit
Country European Union (EU)
Start 12/2016 
End 03/2017
 
Description International Graduate Research Scholarship
Amount £72,000 (GBP)
Organisation Government of Malaysia 
Sector Public
Country Malaysia
Start 04/2014 
End 03/2017
 
Description UNESCO-Loreal Co-sponsored International Fellowship
Amount £50,000 (GBP)
Organisation United Nations Educational, Scientific and Cultural Organization (UNESCO) 
Sector Public
Country Global
Start 04/2010 
End 03/2012
 
Description Wellcome Trust/ Birkbeck Anniversary Graduate Research Scholarship
Amount £85,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2016 
End 03/2019
 
Title Deposition of 3D protein structural information to the Protein Data Bank 
Description Solved the structure of three mycobacterial proteins/ complexes and deposited to the protein databank (PDB: 2XW7, 2WTZ & 2XJA) 
Type Of Material Biological samples 
Year Produced 2010 
Provided To Others? Yes  
Impact Inter-disciplinary research collaboration. Initiation of designing specific small molecule inhibitors. 
URL http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=2XW7
 
Title High throught put enzyme assay for inhibitor screening 
Description A high-throughput (96 well plate based), non-radioactive biological assay for ATP-dependent Mur ligases (a validated target for novel anti-TB drugs) from Mycobacterium tuberculosis has been developed. 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact Inter-disciplinary research collaborations 
URL http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0060143
 
Title Whole cell screening of inhibitors against the growth of mycobacteria (HT-SPOTi) 
Description Rapid assay (HT-SPOT inhibition assay; 96 well) to test a large number inhibitors against the slow growing mycobacteria including M. tuberculosis. 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact Interdisciplinary research collaboartion, a successful Austrian Research Fund Grant and a numeber of joint research publications. 
URL http://bmjopen.bmj.com/content/3/6/e002672.long
 
Description Computational Biology (Bioinformatics), ISMB 
Organisation Birkbeck, University of London
Department Department of Biological Sciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution we supplied the structural information of ATP dependent MurE ligase from M. tuberculosis and the structures of MurE ligase inhibitors and theirs analogues.
Collaborator Contribution Supervised a PhD student in my group on molecular docking of M. tuberculosis MurE inhibitors.
Impact An interdisciplinary collaboration between computational biology and molecular microbiology generated an original research article (published): Guzman. J-D.; Wube, A.; Evangelopoulos, D.; Gupta, A.; Hüfner, A.; Basavannacharya, C.; Raman, M. M.; Thomaschitz, C.; Bauer, R.; McHugh, T.D.; Nobeli, I.; Prieto, J. M.; Gibbons, S.; Bucar, F.; and Bhakta, S. (2011) Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics. J. Antimicrob. Chemotherapy 66(8):1766-72.
Start Year 2010
 
Description Industrial co-operation_Domainex 
Organisation Domainex
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution A high-throughput assay available for evaluation of compounds against ATP-dependent Mur Ligases and Murein Peptide Ligase in Mycobacterium tuberculosis.
Collaborator Contribution Design specific inhibitors of the ATP-dependent MurE ligase in M. tuberculosis.
Impact This academic-industrial partnership is interdisciplinary and complementary.
Start Year 2014
 
Description Inhibitors of Cell wall PG (Med Chem) 
Organisation University College London
Department Department of Chemistry
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution evaluation of the biological properties of the novel compounds against the whole mycobacterial cell as well as against the target enzymes (ATP dependent mur ligases). Currently supervising an interdisciplinary PhD student. A joint UK patent application and an original research article are under review.
Collaborator Contribution Synthesized novel derivatives (more than 100) of aporphine alkaloids as antituberculars.
Impact An interdisciplinary collaboration in between medicinal chemistry, molecular microbiology and chemical biology. Resulted in successful joint supervision of one PhD student, two post-graduate project students, three original research articles and a joint patent application.
Start Year 2011
 
Description NCEs and new formulations to tackle MDR-TB_India 
Organisation Institute of Chemical Technology (ICT)
Country India, Republic of 
Sector Academic/University 
PI Contribution Comprehensive evaluation of biological properties of pure natural product compounds against whole mycobacterial cell, drug efflux mechanisms and biofilm formation as well as against the target enzymes (such as ATP dependent mur ligases, Muerin peptide ligase, Arylamine N-acetyltransferase, Oxidoreductases from M. tuberculosis).
Collaborator Contribution Generated novel chemical entities and pharmaceutical formulations for testing their anti-TB properties and investigating modes of action
Impact An interdisciplinary collaboration between pharmaceutical science and molecular microbiology & biochemistry. A joint split-site commonwealth proposal application is currently under review.
Start Year 2013
 
Description Natural Product Chemistry UCL-SOP 
Organisation University College London
Department School of Pharmacy
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution evaluation of the biological properties of the crude extracts, partially purified fractions, pure natural product compounds against the whole mycobacterial cell as well as against the target enzymes (ATP dependent mur ligases). Jointly supervised two interdisciplinary Bloomsbury PhD students and currently supervising two international (Govt funded) PhD students. Generated 9 joint original research publications, 1 review article and a few others under preparation.
Collaborator Contribution training and advice on extraction, purification and charaterisation of natural products. Contributing to a library of natural products inhibitors for a comprehensive biological evaluation.
Impact An interdisciplinary collaboration in between natural product chemistry, medicinal chemistry and molecular microbiology: Original research articles: 1. Guzman, J.D.; Mortazavi, P.N.; Munshi, T.; Evangelopoulos, D.; McHugh, T.D.; Gibbons, S.; Malkinson, J. and Bhakta, S. (2014) 2-Hydroxy-substituted cinnamic acids and acetanilides are selective growth inhibitors of Mycobacterium tuberculosis. ChemMedComm 5 (1) 47 - 50. 2. Shiu WK, Malkinson JP, Rahman MM, Curry J, Stapleton P, Gunaratnam M, Neidle S, Mushtaq S, Warner M, Livermore DM, Evangelopoulos D, Basavannacharya C, Bhakta, S., Schindler BD, Seo SM, Coleman D, Kaatz GW, Gibbons S. (2013) A new plant-derived antibacterial is an inhibitor of efflux pumps in Staphylococcus aureus. Int J Antimicrob Agents. 42(6):513-8. 3. Guzman JD, Evangelopoulos D, Gupta A, Birchall K, Mwaigwisya S, Saxty B, McHugh TD, Gibbons S, Malkinson J, Bhakta S.* (2013) Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay. BMJ Open, 3(6). 4. Guzman JD, Evangelopoulos D, Gupta A, Prieto JM, Gibbons S. and Bhakta S. (2013) Antimycobacterials from Lovage Root (Ligusticum officinale Koch). Phytotherapy Research, 27(7):993-8. 5. Wube, A.; Guzman, J.D.; Hüfner, A.; Hochfellner, C.; Blunder, M.; Bauer, R.; Gibbons, S.; Bhakta, S. and Bucar, F. (2012) Synthesis and biological evaluation of a new series of N-alkyl-2-alkynyl-4-(1H)-quinolones. Molecules 17(7):8217-40.1. 6. Osman, K., Evangelopoulos, D., Basavannacharya, C., Gupta, A., McHugh, T.D., Bhakta, S. and Gibbons, S. (2012) An antibacterial from Hypericum acmosepalum inhibits ATP dependent MurE ligase from Mycobacterium tuberculosis. Int. J. Antimicrob. Agents. 39(2):124-9. 7. Guzman, J.D., Wube, A., Evangelopoulos, D., Gupta, A., Hüfner, A., Basavannacharya, C., Rahman, M.M., Thomaschitz, C., Bauer, R., McHugh, T.D., Nobeli, I., Prieto, J.M., Gibbons, S., Bucar, F.¶ and Bhakta, S.¶* (2011) Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics. J. Antimicrob. Chemotherapy 66(8):1766-72. (¶ equal contribution). 8. Guzman, J.D.; Gupta, A.; Evangelopoulos, D.; Basavannacharya, C.; Pabon, L.C.; Plazas, E.A.; Muñoz, D.R.; Delgado, W.A.; Cuca, L.E.; Ribon, W.; Gibbons, S. and Bhakta, S.* (2010) Anti-tubercular screening of natural products from Colombian plants: 3-5 methoxy nordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis. J. Antimicrob. Chemotherapy 65(10), 2101-7. 9. O'Donnell, G., Poeschl, R., Zimhony, O., Gunaratnam, M., Moreira, J.B., Neidle, S., Evangelopoulos, D., Bhakta, S., Malkinson, J.P., Boshoff, H.I., Lenaerts, A. & Gibbons, S. (2009). Bioactive pyridine-N-oxide disulfides from Allium stipitatum. J Nat Prod. 72(3), 360-5. Review Article: 1. Guzman, J.D.; Gupta, A.; Bucar, F.; Gibbons, S. and Bhakta, S. (2012) Anti-mycobacterials from natural sources: ancient times, antibiotic era and novel scaffolds. Frontiers in Bioscience 17, 1861-1881.
Start Year 2007
 
Description Natural Product Chemistry_Austria (EU) 
Organisation Medical University of Graz
Department Pharmacognosie Graz
Country Austria, Republic of 
Sector Academic/University 
PI Contribution Comprehensive evaluation of the biological properties of pure natural product compounds against the whole mycobacterial cell, drug efflux mechanisms and biofilm formation as well as against the target enzymes (ATP dependent mur ligases). Generated three joint research publications, a review article and a few others in preparation.
Collaborator Contribution Extract, fractionate, purify, semi-synthesize natural product inhibitors against whole cell mycobacteria as well as the target enzymes for validation.
Impact A multi-disciplinary international collaboration (Natural Product Chemistry & Molecular Microbiology) generated the following outputs/ outcomes: Original Research Articles: 1. Wube, A.; Guzman, J.D.; Hüfner, A.; Hochfellner, C.; Blunder, M.; Bauer, R.; Gibbons, S.; Bhakta, S. and Bucar, F. (2012) Synthesis and biological evaluation of a new series of N-alkyl-2-alkynyl-4-(1H)-quinolones. Molecules 17(7):8217-40. 2. Guzman. J-D.; Wube, A.; Evangelopoulos, D.; Gupta, A.; Hüfner, A.; Basavannacharya, C.; Raman, M. M.; Thomaschitz, C.; Bauer, R.; McHugh, T.D.; Nobeli, I.; Prieto, J. M.; Gibbons, S.; Bucar, F.; and Bhakta, S.* (2011) Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics. J. Antimicrob. Chemotherapy 66(8):1766-72. 3. Wube, A.; Guzman, J.D.; Hüfner, A.; Hochfellner, C.; Blunder, M.; Bauer, R.; Gibbons, S.; Bhakta, S. and Bucar, F. (2012) Synthesis and biological evaluation of a new series of N-alkyl-2-alkynyl-4-(1H)-quinolones. Molecules 17(7):8217-40. Review Article: Guzman, J.D.; Gupta, A.; Bucar, F.; Gibbons, S. and Bhakta, S.* (2012) Anti-mycobacterials from natural sources: ancient times, antibiotic era and novel scaffolds. Frontiers in Bioscience 17, 1861-1881. Joint Research Grant applications (successful): 1. Austrian Science Fund (FWF) 2012 - 2015 (€311K) Co-Apl [4-(1H)-Quinolone derivatives as new antibacterial drug-leads. Austrian Science Fund (FWF), EU] 2. Austrian Science Fund (FWF) 2008 - 2011 (€250K) Co-Apl [The evaluation of 4(1H)-quinolone derivatives as new anti-mycobacterial drug-leads. Austrian Science Fund (FWF): EU project P21152-B18]
Start Year 2008
 
Description New antituberculars with novel MoA_Durham 
Organisation Durham University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Comprehensive evaluation of the biological properties of pure natural product compounds against the whole mycobacterial cell, drug efflux mechanisms and biofilm formation as well as against the target enzymes (ATP dependent mur ligases, N-acetyl transferase, Oxido-reductases). Generated three joint research publications. One review article and a few other research articles are in preparation.
Collaborator Contribution Extract, fractionate, purify, semi-synthesize as well as design natural product inhibitors against target enzymes as well as against whole cell phenotype for validation.
Impact An interdisciplinary academic research collaboration (Natural Product Chemistry, Computational Biology & Molecular Microbiology) generated original research articles and a successful small research grant. One review article is currently in preparation Original Research Articles: 1. Kottakota SK, Benton M, Evangelopoulos D, Guzman JD, Bhakta S, McHugh TD, Gray M, Groundwater PW, Marrs EC, Perry JD and Harburn JJ. (2012) Versatile routes to marine sponge metabolites through benzylidene rhodanines. Org Lett.;14(24):6310-3. 2. Kottakota, S.K.; Evangelopoulos, D.; Alnimr, A.; Bhakta, S.; McHugh, T.D.; Gray, M.; Groundwater, P.W.; Marrs, E.C.L.; Perry, J.D.; Spilling, C.D. and Harburn, J.J. (2012) Synthesis and biological evaluation of Purpurealidin E-derived marine sponge metabolites: Aplysamine-2, Aplyzanzine A, Suberedamines A,B and Anomoian A. J. Nat Prod. 75(6):1090-101.
Start Year 2011
 
Description Novel nano-particulate formulations to tackle MDR-TB_Malaysia 
Organisation Universiti Putra Malaysia
Country Malaysia 
Sector Academic/University 
PI Contribution Comprehensive evaluation of biological properties of novel nano-particulate formulations against mycobacterial whole-cell, drug efflux mechanisms and biofilm inhibitions and a panel of endogenous targets.
Collaborator Contribution Generated novel pharmaceutical formulations for testing their anti-TB properties and investigating anti-mycobacterial modes of action.
Impact an original research article and an international research grant application are currently in preparation.
Start Year 2016
 
Description Reversing antimicrobial resistance in TB 
Organisation King's College London
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Whole-cell phenotypic evaluation of novel chemical entities and target-based evaluation against recombinant proteins from Mycobacterium tuberculosis.
Collaborator Contribution Synthesis of novel chemical entities and their analogues.
Impact Two research articles published. One patent application submitted.
Start Year 2013
 
Description Structural Biology, Birkbeck 
Organisation Birkbeck, University of London
Department Department of Biological Sciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution significant intellectual input into our common research interest in cell wall peptidoglycan biosynthesis, degradation and recycling in Mycobacterium tuberculosis; Supervised three PhD Students (awarded PhDs in between 2010 and 2013) worked on structural and functional characterisation of mycobacterial proteins. Generated four original research articles and a few others are in preparation.
Collaborator Contribution Training and advice on setting crystallisation trials and solving X-Ray diffraction data for 3D structural elucidation of mycobacterial proteins
Impact An interdisciplinary collaboration in between Structural Biology and Molecular Microbiology: Original Research Articles: 1. Basavannacharya, C., Robertson, G., Munshi, T., Keep, N.H. & Bhakta, S. (2010). ATP-dependent MurE ligase in Mycobacterium tuberculosis: biochemical and structural characterisation. Tuberculosis (Edinb) 90(1), 16-24. 2. Basavannacharya, C., Moody, P. R., Munshi, T., Cronin, N., Keep, N. H. & Bhakta, S. (2010). Roles of amino acid residues essential for the enzyme activity of MurE of Mycobacterium tuberculosis identified. Protein & Cell 1(10)(accepted in press; featured as cover page article) 3. Evangelopoulos D, Cronin N, Daviter T, Sim E, Keep NH and Bhakta S. (2011) Characterization of an oxidoreductase from the arylamine N-acetyltransferase operon in Mycobacterium smegmatis. FEBS J. 278(24):4824-32. 4. Munshi, T.; Gupta, A.; Guzman, J. D.; Evangelopoulos, D.; Gibbons, S.; Keep, N.H. and Bhakta, S.* (2013) Characterisation of ATP-Dependent Mur Ligases Involved in the Biogenesis of Cell Wall Peptidoglycan in Mycobacterium tuberculosis. PloS ONE 8(3): e60143. doi:10.1371/journal.pone.0060143
Start Year 2006
 
Description Substrates and analogues of cellwall-PG enzymes 
Organisation University College London
Department School of Pharmacy
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution assaying the activity and inhibition of substrates and substrate analogues against ATP-dependent Mur ligases and Murein peptide ligases from bacteria.
Collaborator Contribution Synthesizing substrates and substrate analogues (using solid phase peptide synthesis)
Impact An interdisciplinary collaboration in between synthetic chemistry and molecular microbiology. A PhD student is currently under joint supervision and generated one review article and one research article currently in preparation.
Start Year 2011
 
Description Traditional herbs and new antibiotic_Strathclyde 
Organisation University of Strathclyde
Department Department of Physics
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Bioassay guided whole-cell phenotypic and genotypic evaluation of natural products (crude extracts, partially purified fractions and purified molecules).
Collaborator Contribution provide natural product inhibitors (crude extracts , partially purified fractions and pure compounds) for bioassay guided evaluation against a panel of bacterial pathogens.
Impact This is an interdisciplinary collaboration between traditional herbal natural products and microbiology. Generated one original research article and one article in preparation. In addition, a joint cross-council research grant application (submitted and under review). Original Research Article: 1. Zhao J, Evangelopoulos D, Bhakta S, Gray AI and Seidel V. (2014) Antitubercular activity of Arctium lappa and Tussilago farfara extracts and constituents. J Ethnopharmacol.;155(1):796-800.
Start Year 2011
 
Title "Tetrahydroisoquinolines as Antimicrobials" (UCLB ref: 23-072) 
Description new biologically active chemical entities with novel mechanisms of action as antimicrobials to tackle the drug resistance in infectious diseases primarily TB. 
IP Reference INSUFFICIENT INFORMATION 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact Novel hits for anti-TB drug design.
 
Title A high throughput assay for ATP dependent MurE ligase of Mycobacterium tuberculosis 
Description A high-throughput (96 well format) non-radioactive biological assay for ATP-dependent Mur ligases from M. tuberculosis has been developed to determine the activity and/or inhibition of the target enzyme. 
IP Reference  
Protection Protection not required
Year Protection Granted 2012
Licensed No
Impact Availability of this assay is highly beneficial for TB inihibitor screening purposes and identifying novel mode of action for novel chemical entities. A number of academic research collaboration to be established on the basis of this facility.
 
Title New antitubercular compounds 
Description Novel pyrroles have been designed, synthesized and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the anti-tubercular drugs BM212 1 and SQ109 2 that showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multi-drug resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) towards the whole-cell drug efflux pump activity of mycobacteria, and thus turning to be promising multi-drug resistance reversal agents. 
IP Reference  
Protection Patent application published
Year Protection Granted 2015
Licensed Commercial In Confidence
Impact Potentially address the major health challenge globally to tackle the rise of antimicrobial resistance.
 
Title Whole cell screening of inhibitors against the growth of mycobacteria (HT-SPOTi) 
Description A solid culture based whole cell screening assay (HT-SPOTi; 24, 48 & 96 well format) to test libraries of inhibitors against the slow growing mycobacteria including Mycobacterium aurum and Mycobacterium tuberculosis. 
IP Reference  
Protection Protection not required
Year Protection Granted 2012
Licensed No
Impact Availability of this whole cell screening assay is highly beneficial for TB inihibitor screening purposes. A large number of academic & industrial research collaborations to be established on the basis of this facility.
 
Title Use of NSAIDs in novel anti-TB combination therapy 
Description Studying molecular modes of anti-tubercular actions of NSAIDs. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2013
Development Status Actively seeking support
Impact Not applicable. 
URL http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693423/
 
Title Whole cell assay for testing inhibitor and rapid daignosis of drug resistance profile 
Description This in vitro whole cell inhibitor screening model is developed for drug/ inhibitor screenig in an efficient and higher through put format. An UNESCO-Loreal International Fellowship is awarded to the research group to develop this model. Further support is required for the further development of this product. 
Type Support Tool - For Medical Intervention
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Actively seeking support
Impact A large number of chemicals screened in rapid but for a gold standard output. A number of research collaborations and joint publications have arisen and a joint research grant application is under preparation. 
URL http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693423/
 
Description After-School Science Project "TB or not TB" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Senior School girls engaged with an after school science club project entitled "TB or not TB", visited local pharmacy to buy over the counter medicines for investigating their potential to be repurposed. Designed and performed wet-lab experiments, observed results, recorded data, presented report and a film to the public and British Institute of Technology and achieved "The most creative school award 2015" for the successful completion and execution of the science project. The award was formally collected from the House of Lords.
Year(s) Of Engagement Activity 2015,2016
URL http://www.bbk.ac.uk/news/tb-project-wins-bite-title
 
Description Birkbeck School of Science Week 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Film screening and panel discussion: Tackling antibiotic resistance and the rise of superbugs at Birkbeck Cinema, 43 Gordon Square, London, WC1H 0PD
Antibiotics were first mass-produced in the 1940s and their ability to fight and kill bacteria revolutionized medicine and profoundly impacted everything from agriculture to war. After less than 80 years, however, these miracle drugs are failing. Resistant infections kill hundreds of thousands of people around the world each year and there are now dozens of so-called Superbugs each with its own challenges and costs. How did this happen? Using microscopic footage, harrowing personal stories, and expert insights, Resistance clarifies the problem of antibiotic resistance, how we got to this point, and what we can do to turn the tide.
Year(s) Of Engagement Activity 2017
URL http://www.bbk.ac.uk/science/about-us/events/science-week/
 
Description Public Lecture; article as part of a large Community Event 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact around 200 people attended the workshop, asked questions, discussion and feedback taken afterwards. 5000 printed copies of the published brochure was freely distributed to the public and also made available online to read.

awareness of Tuberculosis (TB) control strategies to the general public:
http://principlesofproteinstructure.blogspot.com/2011/04/structural-biology-in-fight-against-tb.html; http://www.tbd-uk.org.uk/news-items/world-tb-day-summary.html;
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
URL http://www.londonsu.org/
 
Description STEMNET/ Researcher in Residence (School Visit) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact A total of around 40 sixth formers and children on the Gifted and Talented Programme at St Mary's School, Bucks were learning about the germ that cause tuberculosis. I had been discussing my research on tuberculosis, and looking at how the disease is transmitted and spread, the rise of antibiotic resistance and the need to develop new drugs to combat the disease. The girls participated in a science club, combining scientific lectures with practical experience, for example on how to observe bacteria under a microscope, carried out observations, submitted practical reports and feedback on their findings. In addition I demonstrated the research methods we routinely use in the lab for determining whether any novel chemicals have medicine-like properties, using equipment from my laboratory, and a Science Technician from the named School, visited my lab to study the specific techniques used there prior to the school project.

The RinR programme has proved hugely popular with parents, teachers and pupils and the aim is to establish a longer term relationship between the School and the University, so that future generations of girls can be switched onto science.

Relevant Press Releases:
http://www.scienceoxfordnext.com/stem-news-articles/researcher-in-residence-switches-schoolgirls-onto-science; http://gerrardscross.buckinghamshireadvertiser.co.uk/2011/09/top-biologist-starts-residence.html;
http://www.bbk.ac.uk/news/researcher-in-residence-switches-schoolgirls-onto-science;
http://www.ps-magazine.co.uk/news.htm; http://www.stmarysschool.co.uk/news/RinRAutumn2011.htm
Year(s) Of Engagement Activity 2011,2012,2013,2014
URL http://www.bbk.ac.uk/news/researcher-in-residence-switches-schoolgirls-onto-science
 
Description Social Media Public Engagement 
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 620 people like the webpage and follow the posts, posts related to TB research and outreach activities reach about 1500 people every week.
Year(s) Of Engagement Activity 2015,2016,2017
URL https://www.facebook.com/TBrnotTB/
 
Description WGND Interview (Podcast) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact public interest and enquiris on the TB drug discovery research following the podcast.

Following the podcast interview:
(a) a local school showed interest developing a afterschool science club to perform some tests and discuss antibiotic resistance in TB.
(b) an international media enquired about new drug testing platform developed and possibility of using this technique in resource poor settings in India.
Year(s) Of Engagement Activity 2011
URL http://www.newtbdrugs.org/blog/podcast-interview-with-dr-sanjib-bhakta/
 
Description World TB Day (Bloomsbury Public Event) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact series of public lectures, poster presentations, screening a film on TB awareness: "The Real Story" by TB Alert and panel discussions were enthusiastically attended by a housefull of 200 in the audience and participated in the questions and discussions throughout the day.

The event was supported and posted by a number of national and international TB organisations and charities. A large group of sixth form pupils attended the event and showed keen interest in the science activity.

Relevant Press Releases:
http://cms1.its.bbk.ac.uk/news/news-releases/world-tuberculosis-day
http://principlesofproteinstructure.blogspot.com/2011/04/structural-biology-in-fight-against-tb.html; http://www.tbd-uk.org.uk/news-items/world-tb-day-summary.html

http://www.bbk.ac.uk/biology/about-us/oldevents/world-tuberculosis-day-2012

http://www.worldtbday.org/idf-at-birkbeck/
Year(s) Of Engagement Activity 2010,2011,2012