MICA: New combination therapy against MDR TB targeting the respiratory chain

Lead Research Organisation: Liverpool School of Tropical Medicine
Department Name: Tropical Disease Biology

Abstract

Tuberculosis (TB) is the main cause of deaths related to antimicrobial resistance. In 2016, there were an estimated 10.4 million new TB cases worldwide, and 1.7 million TB-associated deaths. Multi -drug-resistant (MDR) TB is on the rise and globally, the average cure rate for MDR-TB is only 54% and only 30% for extensively drug resistant TB (XDR-TB). TB is a disease of poverty and presently, 95 % of the TB-related deaths occur in LMICs. The proposed activities are primarily and directly relevant to the health needs of LMIC and therefore ODA compliant

New combination therapies that can overcome current resistance mechanisms are urgently required. Here, we wish to validate an exciting new therapeutic approach of targeting multiple respiratory chain components of Mycobacterium tuberculosis, the causative pathogen of TB. The co-investigators, assembled from both academia and the pharmaceutical industry, are uniquely placed to exploit this strategy possessing (i) extensive domain expertise, (ii) proprietary compound libraries containing selective inhibitors of 4 key respiratory chain components, (iii) access to validated in vitro and in vivo models for assessment of efficacy for drug combinations and (iv) background intellectual property (IP) to both inhibitors and the combinatorial approach. Our objective is to gain validation of this approach using gold-standard in vitro and vivo disease models of TB and to identify the combination of targets eliciting the optimal antitubercular effect which are most likely to be of value in the clinic. In addition, we will also investigate the potential of inhibitor combinations, in reducing the emergence of new drug resistance, thus potentially extending the lifetime of any new therapeutic solution.

The resulting information will inform and aid in prioritization of drug discovery and development programs that aim to identify inhibitors of respiratory chain components that, when used together, should contribute sterilizing activity to novel drug regimens for MDR-TB, resulting in shorter treatment times for patients. Ongoing discovery programs that will directly benefit from the research output include our own and those of our industrial partner; in addition, we expect the data generated to inspire additional TB discovery and development programs in the wider TB community.

Technical Summary

Our strategy is to validate a new combination therapy approach that targets components of the M. tuberculosis (Mtb) respiratory chain, specifically cytochromes bcc and bd, ndh2 dehydrogenase and ATP synthase. Targeting the respiratory chain has been shown by us and by others, to be effective in killing both replicating and dormant Mtb, leading to sterilization of cultures in vitro, as well as cure of TB-infected animals and clinical efficacy. Because there is no known pre-existing resistance due to mutations in genes encoding respiratory chain components, drugs targeting these enzymes would be effective against MDR-TB. Bedaquiline, a new TB drug targeting ATP synthase, demonstrates bactericidal activity in MDR TB patients, providing clinical validation for ATP synthase and respiratory targets more broadly. TB treatment always consists of multi-drug regimens, to maximize efficacy and minimize emergence of resistance to individual drugs. Recent data, including our own, indicates that simultaneous targeting of more than one component of the respiratory chain, can result in a synergistic and dramatic bactericidal effect. Through our medicinal chemistry programs, we have identified several compounds that inhibit each respiratory chain component. With our collaborators, we have also developed predictive in vitro and in vivo assays, which comprise an ideal tool box for evaluation of this combination-targeting concept. We propose to leverage our unique domain expertise, combination of tools and compounds to identify the most promising target pairs or groups and to provide critical pharmacological validation. We will also use pharmacokinetic-pharmacodynamic modelling to determine whether synergistic/additive anti-Mtb activity we demonstrate, is predicted to lead to clinically measurable benefits. Finally, we will evaluate whether the described combination strategy has the potential to overcome existing resistance mechanisms and reduce the emergence of de novo resistance.

Planned Impact

In 2016, 10.4 million people fell ill with TB, and 1.7 million died from the disease, including 250 000 children. TB is a disease of poverty with over 95% of TB deaths occurring in low- and middle-income countries (LMIC). Multidrug-resistant TB (MDR-TB) remains a public health crisis. The WHO estimates that there were 600 000 new cases with resistance to rifampicin - the most effective first-line drug, of which 490 000 had MDR-TB.

The treatment for tuberculosis (TB) relies on drugs developed some 40 years ago. There are a number of shortcomings with these drugs including (i) long treatment regimens (6 to 9 months) leading to patient non-compliance, (ii) adverse drug-drug interactions with anti HIV drugs (HIV/AIDS is a common co-infection) and (iii) limited or no activity against MDR and extensively drug resistant (XDR) Mycobacterium tuberculosis (Mtb).

In this project, we are responding to the specific call from the international medical community to validate a new antitubercular drug combination strategy, which we hope will lead to the development of a new combination therapy to treat MDR-TB patients. If validated, this strategy could represent a step-change in antitubercular chemotherapy, delivering a novel therapeutic intervention with the potential to target slow-growing/persistent bacilli, leading to shorter treatment regimens, whilst the novel mechanisms of action would be able to overcome current resistant mechanisms and have utility to treat MDR-TB patients. A faster, simpler cure for TB will save lives and have tremendous global benefits. A shorter TB regimen would also improve treatment compliance (and so reduce the likelihood of drug-resistant strains); broaden the reach of DOTS; and allow more patients to be treated

Publications

10 25 50

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Donnellan S (2023) A Quantitative Method for the Study of HIV-1 and Mycobacterium tuberculosis Coinfection. in The Journal of infectious diseases

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Neary M (2023) Quantitation of tizoxanide in multiple matrices to support cell culture, animal and human research. in Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

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Rajoli RK (2020) Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. in medRxiv : the preprint server for health sciences

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Rajoli RKR (2021) Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. in British journal of clinical pharmacology

 
Description Findings are still being generated, with some publications already delivered. Given the nature of the award, it is too early to make impact statements with this discovery translational award.
Exploitation Route Findings are still being generated - it is too early to make statements of future work at this stage but clearly our findings will have relevance to future TB drug discovery initiatives by academia, industry and public development partnerships (PDPs).
Sectors Healthcare

Pharmaceuticals and Medical Biotechnology

 
Description : Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and tar get site concentrations derived from their established human pharmac okinetics. Clin Pharmacol Ther 2020;108(4):775-790
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO policy
URL https://iris.who.int/bitstream/handle/10665/365584/WHO-2019-nCoV-therapeutics-2023.1-eng.pdf?sequenc...
 
Description Arshad U, Pertinez H, Box H, Tatham L, Rajoli RKR, Curley P, et al. Prioritization of -nti-SARS-Cov-2 7rug uepurposing opportunities 0ased on rlasma and |arget vite 1oncentrations 7erived from their ;stablished _uman rharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO policy
URL https://iris.who.int/bitstream/handle/10665/342368/WHO-2019-nCoV-therapeutics-2021.2-eng.pdf?sequenc...
 
Description Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO policy
URL https://iris.who.int/bitstream/handle/10665/340374/WHO-2019-nCoV-therapeutics-2021.1-eng.pdf?sequenc...
 
Description Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO policy
URL https://iris.who.int/bitstream/handle/10665/353403/WHO-2019-nCoV-therapeutics-2022.3-eng.pdf?sequenc...
 
Description Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO Policy
URL https://iris.who.int/bitstream/handle/10665/345356/WHO-2019-nCoV-therapeutics-2021.3-eng.pdf?sequenc...
 
Description Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO policy
URL https://iris.who.int/bitstream/handle/10665/351006/WHO-2019-nCoV-therapeutics-2022.1-eng.pdf?sequenc...
 
Description Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO policy
URL https://iris.who.int/bitstream/handle/10665/350177/WHO-2019-nCoV-therapeutics-2021.4-eng.pdf?sequenc...
 
Description Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO policy
URL https://iris.who.int/bitstream/handle/10665/359774/WHO-2019-nCoV-therapeutics-2022.4-eng.pdf?sequenc...
 
Description Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790.
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Has informed WHO policy
URL https://iris.who.int/bitstream/10665/362843/1/WHO-2019-nCoV-therapeutics-2022.5-eng.pdf
 
Description Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin Pharmacol Ther 2020;108(4):775-790.
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Informed WHO policy
URL https://iris.who.int/bitstream/handle/10665/352285/WHO-2019-nCoV-therapeutics-2022.2-eng.pdf?sequenc...
 
Description Expanding Excellence
Amount £9,843,478 (GBP)
Organisation United Kingdom Research and Innovation 
Sector Public
Country United Kingdom
Start 07/2024 
End 07/2029
 
Description Institutional Partnership Awards 'LSTM translational enabler'
Amount £300,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2022 
End 03/2023
 
Description MRC Translational and Quantitative Skills Doctoral Training Programme in Global Health
Amount £500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2021 
End 03/2025
 
Description Research England Connecting Capability Fund: Bloomsbury SET Impact Connector Consortium
Amount £1,900,000 (GBP)
Organisation United Kingdom Research and Innovation 
Sector Public
Country United Kingdom
Start 03/2021 
End 03/2022
 
Description Translational Development Fund
Amount £2,700,000 (GBP)
Organisation LifeArc 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2023 
End 03/2025
 
Description Translational and Quantitative Skills Doctoral Training Programme in Global Health
Amount £1,950,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2021 
End 03/2028
 
Description CN-Bio Development of Infection Organoids 
Organisation CN Bio Innovations Ltd
Country United Kingdom 
Sector Private 
PI Contribution Collaboration with CN-Bio for the development of Infection Organoids. CN-Bio provide the platforms and we provide the infection expertise and apply it to the development of a platform suitable for biological and translational investigations.
Collaborator Contribution Collaboration with CN-Bio for the development of Infection Organoids. CN-Bio provide the platforms and we provide the infection expertise and apply it to the development of a platform suitable for biological and translational investigations.
Impact The collaboration is still generating new data/information. The multi-disciplinary approach involves teams with expertise in cell/tissue engineering, infection and therapeutics discovery.
Start Year 2021
 
Description Newcells - LSTM Development of Infection Organoids 
Organisation Newcells Biotech
Country United Kingdom 
Sector Private 
PI Contribution Development of an organoid-infection model for SARS-CoV2
Collaborator Contribution Development of an organoid-infection model for SARS-CoV2
Impact Joint publication and funding applications
Start Year 2020
 
Description Rosalind Franklin Institute 
Organisation Rosalind Franklin Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We have been able to support the application of a new tool developed by RFI for TB in vivo imaging. We hope that the collaboration will develop an MHRA approved tool that can be used to support the clinical management of TB and non-TB mycobacterial infections.
Collaborator Contribution RFI have developed the innovative technology and our role in the collaboration is to support the development of the technology towards having societal impact.
Impact A collaboration agreement is being developed and pathway to impact has been undertaken.
Start Year 2023
 
Description TB Alliance 
Organisation The Global Alliance for TB Drug Development
Country Global 
Sector Private 
PI Contribution We have developed inhibitors via the MRC funded project that are at lead stage - these are being tested presently. We are also in discussions with TBA regarding our high content imaging platform, the development of which is supported via a MRC CiC award
Collaborator Contribution TBAlliance have conducted in vivo PK studies on our lead compounds and we will shortly be conducting in vivo drug efficacy experiments using their TB drug development network If successful this will form the basis of a more extensive drug development programme
Impact TBAlliance are providing support in the way of in vivo PK and TB in vivo drug efficacy models (rodent acute model) If successful this will form the basis of a more extensive drug development programme
Start Year 2014
 
Description TB Research Collaboration with University of Oxford 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration in TB Area of Research
Collaborator Contribution Collaboration in TB Area of Research
Impact Collaboration in TB Area of Research
Start Year 2023