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

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"This AMR TDV Preliminary Award, is linked to the main study entitled “New combination therapy against MDR TB targeting the respiratory chain” and will be used to primarily to;

(i) Undertake additional target validation experiments,
(ii) Support long-lasting collaborations with collaborators including those from LMICs, and
(iii) Support engagement with industry.

As described in the accompanying Case for Support, target validation activities will include; (a) Assessment of quinone-redox-poise with simultaneous O2-consumption by Mycobacterium respiratory membranes in the presence and absence of respiratory inhibitors both as single agents and in combinations. This work will be undertaken with an industrial partner, Oroboros Instruments, and will afford a unique opportunity to determine inhibitor selectivity and any potential off-target activities; (b) Assessment of gene expression response in M. tuberculosis following in vitro and in vivo exposure to respiratory inhibitors. This activity will be undertaken in collaboration with Dr Simon Waddell (Microbial Pathogenesis, Sussex University) - It has previously been demonstrated that Mtb gene expression response is very specific according to the type of growth inhibitor to which Mtb is exposed, including inhibitors of respiratory chain. In collaboration with Dr Waddell, we will determine the expression signatures of Mtb in response to selective inhibitors and assess the signatures when drugs are used in combination both during in vitro experiments and during in vivo exposure. These experiments will further inform target validation especially during in vivo (rodent) exposure; (c) Generation of novel squaramide series and biochemical validation of this series and assessment of potential off-target activity of additional respiratory inhibitors, against ATPsynthase. This work will be undertaken in collaboration with Prof. Dirk Bald (Faculty of Science, Structural Biology, Vrije University, Amsterdam). The award will also be used to develop a dynamic network of collaborators with interest in the development of new drug combinations, especially those targeting the respiratory chain, and will involve LMIC partnerships in Africa, South East Asia and South America possessing unique drug resistant isolates, including bedaquiline resistant strains. In addition, the award will facilitate further industry engagement towards the development of public-private partnerships for follow-on drug development of new combination therapies."