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

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.

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.

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