Cambridge-Chennai Centre Partnership on Antimicrobial Resistant Tuberculosis

Lead Research Organisation: University of Cambridge
Department Name: Medicine

Abstract

The need for a joint India-UK Centre Partnership focused on drug-resistant tuberculosis (TB) is founded on the scale of the problem both in India and globally, combined with the pressing need to develop new tools and therapeutics to combat it. There were 1,467,585 cases of TB notified in India during 2012 (the largest number of cases in any country worldwide), with a sharp rise in the number of people diagnosed with multidrug resistant (MDR) TB (from 308 to 16,588 laboratory confirmed cases between 2008 and 2012). Our partnership between the University of Cambridge and the National Institute for Research in Tuberculosis (NIRT) in Chennai, India, will bring together a multidisciplinary team to focus on novel diagnostics and therapeutics for TB. This includes the use of emerging sequence-based diagnostics to improve the accuracy of individual patient treatment for MDR and extensively drug resistant (XDR) TB; new drug targets for TB and prediction/investigation of the impact of resistance mutations based on modelling of bacterial genome data; the development of an in-depth understanding of the bacterial genes in diverse populations of Mycobacterium tuberculosis associated with so-called 'drug tolerance'; and novel approaches to treatment of TB based on immunomodulation (enhancement of autophagy and novel enhancers of T cell responsiveness). The Centre Partnership will generate a rich and lasting clinical and genomic dataset. Our objectives require detailed clinical and biological phenotyping and genotyping of patient cohorts, which can be mined to address future questions and will further enhance collaborative research to tackle the burden of drug-resistant TB. We will also innovate in training and knowledge transfer. Leveraging of novel technologies will increase relevant and collaborative research experience for UK and Indian investigators. Transfer of scientific training and technology to India enhances independent research capacity and fosters future international collaborative projects. This will be achieved through mobility and exchange of junior (training) and senior (discipline-hopping) researchers.

Technical Summary

The need for a joint India-UK Centre Partnership focused on drug-resistant tuberculosis (TB) is founded on the scale of the problem both in India and globally, combined with the pressing need to develop new tools and therapeutics to combat it. There were 1,467,585 cases of TB notified in India during 2012 (the largest number of cases in any country worldwide), with a sharp rise in the number of people diagnosed with multidrug resistant (MDR) TB (from 308 to 16,588 laboratory confirmed cases between 2008 and 2012). Our partnership between the University of Cambridge and the National Institute for Research in Tuberculosis (NIRT) in Chennai, India, will bring together a multidisciplinary team to focus on novel diagnostics and therapeutics for TB. This includes the use of emerging sequence-based diagnostics to improve the accuracy of individual patient treatment for MDR and extensively drug resistant (XDR) TB; new drug targets for TB and prediction/investigation of the impact of resistance mutations based on modelling of bacterial genome data; the development of an in-depth understanding of the bacterial genes in diverse populations of Mycobacterium tuberculosis associated with so-called 'drug tolerance'; and novel approaches to treatment of TB based on immunomodulation (enhancement of autophagy and novel enhancers of T cell responsiveness). The Centre Partnership will generate a rich and lasting clinical and genomic dataset. Our objectives require detailed clinical and biological phenotyping and genotyping of patient cohorts, which can be mined to address future questions and will further enhance collaborative research to tackle the burden of drug-resistant TB. We will also innovate in training and knowledge transfer. Leveraging of novel technologies will increase relevant and collaborative research experience for UK and Indian investigators. Transfer of scientific training and technology to India enhances independent research capacity and fosters future international collaborative projects. This will be achieved through mobility and exchange of junior (training) and senior (discipline-hopping) researchers.

Publications

10 25 50

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Chan DS (2017) Fragment Screening against the EthR-DNA Interaction by Native Mass Spectrometry. in Angewandte Chemie (International ed. in English)

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Malhotra S (2017) TIBLE: a web-based, freely accessible resource for small-molecule binding data for mycobacterial species. in Database : the journal of biological databases and curation

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Malhotra S (2017) TIBLE: a web-based, freely accessible resource for small-molecule binding data for mycobacterial species. in Database : the journal of biological databases and curation

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Malhotra S (2017) Decoding the similarities and differences among mycobacterial species. in PLoS neglected tropical diseases

 
Description Chair, BBSRC (Tom Blundell)
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact The BBSRC has been a leading influence in basic and strategic research underpinning agriculture and food, biotechnology and animal and hum health (one Health)
URL http://www.bbsrc.ac.uk
 
Description Chapter (on pathogen genomics) in Chief Medical Officer Volume II annual report on the tropic of genomics
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description President of UK Science Council (Tom Blundell)
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact As President of Science Council I have overseen the introduction of professional accreditation, such as CSci, in across 40 professional societies. This is a major initiative to recognise the contributions of professional scientists in
URL http://sciencecouncil.org
 
Description Tom Blundell, Guest Lecturer International Chair of Therapeutic Innovation, an initiative of the Laboratory of Excellence in Research on Medication and Innovative Therapeutics: dissemination and training program.
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact Tom Blundell was Guest Lecturer and Discussant for three days in Paris as part of an initiative Medication and Innovative Therapeutics (LERMIT) as part of a dissemination and training program.
URL http://www.labex-lermit.fr/en/formation/chaire-internationale-d-innovation-therapeutique
 
Description Cambridge-Chennai centre partnership on antimicrobial resistant tuberculosis
Amount £1,007,929 (GBP)
Funding ID MR/N501864/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2015 
End 06/2019
 
Description MRC antimicrobial resistance collaboration
Amount £1,588,479 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description UK Rapid Support Team
Amount £11,999,339 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start  
 
Description Wellcome Collaborative Award
Amount £2,341,255 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2019 
End 03/2024
 
Description Wellcome Trust
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2016 
End 03/2020
 
Description Wellcome Trust
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2015 
End 05/2019
 
Title mCSM and mCSMlig 
Description A machine learning approach to understanding the mechanisms by which mutations affect human genetic disease, drug resistance in cancer and antimicrobial resistance in human and infectious disease 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2015 
Provided To Others? Yes  
Impact Demonstration that both genetic disease and drug resistance mechanisms include allosteric and protein interface affects, leading to suggestions about novel therapeutic mechanisms. 
URL http://bleoberis.bioc.cam.ac.uk/mcsm/
 
Title Chopin 
Description Database of the structural proteome of Mycobacterium tuberculosis 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Helpful in understanding the druggability of targets for antibacterials for tuberculosis 
URL http://mordred.bioc.cam.ac.uk/chopin/about
 
Title Credo 
Description A database of protein interactions, including protein-protein, protein ligand 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact Used to understand drug interactions with protein targets 
URL http://marid.bioc.cam.ac.uk/credo
 
Description David Sherman RNAseq 
Organisation Center for Infectious Disease Research
PI Contribution Provision of patient samples from study.
Collaborator Contribution Dr. David Sherman of the Center for Infectious Diseases, Seattle will perform RNA-seq analysis on patient sputum samples obtained from the study so as to examine directly the expression of efflux pumps and their regulators. These RNAs will also be a resource to examine other genes of interest from other projects as needed.
Impact None yet
Start Year 2017
 
Description Identifying targets from phenotypic screening in tuberculosis 
Organisation University of Dundee
Department College of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration Funded by Gates Foundation to identification of new targets for drug discovery arising from phenotypic screens. My team has contributed knowledge, databases and software focusing on protein targets in Mycobacterium tuberculosis
Collaborator Contribution Dundee has contributed software and expertise in medicinal chemistry
Impact Talks in meetings identified elsewhere by various participants. Discussions with HIT-TB Consortium
Start Year 2013
 
Description Shorten-TB 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Country United States 
Sector Public 
PI Contribution Analysis of structure, function and druggability of targets in tuberculosis
Collaborator Contribution Drug screening and development
Impact None yet
Start Year 2017
 
Description Shorten-TB 
Organisation University of Cape Town
Department Institute of Infectious Disease and Molecular Medicine (IIDMM)
Country South Africa 
Sector Academic/University 
PI Contribution Analysis of structure, function and druggability of targets in tuberculosis
Collaborator Contribution Drug screening and development
Impact None yet
Start Year 2017
 
Description Shorten-TB 
Organisation University of Dundee
Department College of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of structure, function and druggability of targets in tuberculosis
Collaborator Contribution Drug screening and development
Impact None yet
Start Year 2017
 
Title mCSM 
Description Machine learning approach to predicting the impacts of mutations on protein stability and interactions with other proteins, nucleic acids, and small molecule ligands. 
Type Of Technology Webtool/Application 
Year Produced 2016 
Impact It has significant impact on understanding mutations in genetic disease and drug resistance 
URL http://bleoberis.bioc.cam.ac.uk/mcsm/
 
Title sdm 
Description An updated webserver for the improved SDM, used for predicting the effects of mutations on protein stability. We have updated the environment-specific amino-acid substitution tables based on the current expanded PDB (a 5 fold increases in information), and introduced new residue conformations and interaction parameters, including packing density and residue depth. 
Type Of Technology Webtool/Application 
Year Produced 2017 
Impact The updated server has been extensively tested using a wide benchmark containing 2690 point mutations from 132 different protein structures. Using an established benchmark, the revised method correlated well against the hypothetical reverse mutations, better than comparable methods built using machine-learning approaches, highlighting the strength of our knowledge-based approach for identifying stabilising mutations. Given a PDB file (a Protein Data Bank file format containing the three-dimensional coordinates of the protein atoms), and a point mutation, the server calculates the stability difference score between the wildtype and mutant protein. 
URL http://structure.bioc.cam.ac.uk/sdm2
 
Description Antimicrobial Resistance Workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Workshop discussing with policy makers, clinicians, scientists and research students in order to understand and cobalt impacts of antimicrobial resistance, mainly in tuberculosis
Year(s) Of Engagement Activity 2016
 
Description BIOINFORMÁTICA ESTRUTURAL DE PROTEÍNAS: MODELOS, ALGORITMOS E APLICAÇÕES BIOTECNOLÓGICAS, Belo Horizonte, Brasil 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A joint Brazil-UK workshop bringing together discussion human genetics and race in Brazil with our analyses of the effects of genome mutations on genetic disease, cancer and antimicrobial resistance
Year(s) Of Engagement Activity 2015
 
Description Indian National Science Congress 2016, Mysore 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact General theme: Science & Technology for Indigenous Development in India. Tom Blundell Plenary Lecturer on Drug discovery for infectious disease in India where budgets have to be low. Open Source Drug Discovery, Biotech Spin-outs and Academia in Research Ecosystems
Year(s) Of Engagement Activity 2016
URL http://www.isc103.in
 
Description Joint Workshop for PhD researchers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Increased use of Genome3D databases and software

Questions from PhD about visiting lab
Year(s) Of Engagement Activity 2014
 
Description Tom Blundell appointed 8th Distinguished Technopreneur 2015, Singapore 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact A discussion by Tom Blundell of research ecosystems, based on experience of forming companies in London and Cambridge, and looking at options for Singapore.

Discussions with Deputy Prime Minister of Singapore; visit of Head of Research to my company on the Science Park
Year(s) Of Engagement Activity 2015
URL http://www.science50.com.sg/dts.html
 
Description Two lectures in University Pretoria, first to broad audience of students, policy makers, teachers; the second to students from the local Ndebele township 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact Lectures leading to small discussions with groups of mainly Ndebele speaking undergraduate students; followed by visit to local township for discussions mediated by Dr Gugu Motshwene, and ex-tudent now lecturer in the University of Pretoria
Year(s) Of Engagement Activity 2016
 
Description Wellcome Trust Sanger Institute Genomics for Clinicians course 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A talk on pathogen genomics to clinical professionals attending a 1 week course to gain an understanding of the application of genomics to clinical practice
Year(s) Of Engagement Activity 2017