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

结核病(TB)是与抗菌素耐药性有关的主要死亡原因。2016年，全球估计有1040万新结核病病例，170万与结核病相关的死亡。耐多药结核病呈上升趋势，在全球范围内，耐多药结核病的平均治愈率仅为54%，广泛耐药结核病的平均治愈率仅为30%。结核病是一种贫困疾病，目前，与结核病有关的死亡有95%发生在低收入国家。拟议的活动主要与低收入国家的健康需求直接相关，因此迫切需要符合官方发展援助的新的联合疗法，以克服目前的耐药机制。在这里，我们希望验证一种令人兴奋的新治疗方法，即针对结核分枝杆菌的多个呼吸链成分，结核分枝杆菌是引起结核病的病原体。来自学术界和制药业的合作研究人员在利用这一战略方面处于独特的地位，他们拥有(I)广泛的领域专业知识，(Ii)包含4个关键呼吸链成分的选择性抑制剂的专有化合物文库，(Iii)获得用于评估药物组合有效性的有效的体外和体内模型，以及(Iv)抑制剂和组合方法的背景知识产权。我们的目标是利用体外和体内结核病的金标准疾病模型来验证这种方法，并确定最有可能在临床上有价值的、能够产生最佳抗结核效果的靶点组合。此外，我们还将调查抑制剂组合在减少新耐药性出现方面的潜力，从而潜在地延长任何新治疗方案的寿命。由此产生的信息将为药物发现和开发计划提供信息并帮助确定优先顺序，这些计划旨在识别呼吸链成分的抑制剂，当它们一起使用时，应有助于为耐多药结核病的新药物方案提供灭菌活性，从而缩短患者的治疗时间。将直接受益于研究成果的正在进行的发现计划包括我们自己和我们工业合作伙伴的计划；此外，我们预计产生的数据将激励更广泛的结核病社区开展更多的结核病发现和开发计划。

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 compliantNew 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.