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

MICA：针对呼吸链的耐多药结核病新联合疗法

• 批准号: MR/S00467X/1
• 负责人: Giancarlo Biagini
• 金额: $ 139.86万
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS00467X%2F1
• 关键词: MICA; New; combination; therapy; against

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.

结核病（TB）是与抗菌素耐药性有关的死亡的主要原因。2016年，全球估计有1040万新发结核病病例，170万结核病相关死亡。耐多药（MDR）结核病正在上升，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（XDR-TB）的平均治愈率仅为30%。结核病是一种贫困疾病，目前，95%的结核病相关死亡发生在中低收入国家。拟议的活动主要直接关系到LMIC的健康需求，因此迫切需要能够克服当前耐药机制的新的联合疗法。在这里，我们希望验证一种令人兴奋的新的治疗方法，靶向结核分枝杆菌，结核病的病原体的多个呼吸链成分。来自学术界和制药行业的共同研究者具有独特的优势来利用这一战略，他们拥有（i）广泛的领域专业知识，（ii）包含4种关键呼吸链组分的选择性抑制剂的专有化合物库，（iii）获得经验证的体外和体内模型，以评估药物组合的功效，以及（iv）背景知识产权抑制剂和组合方法。我们的目标是获得验证这种方法使用金标准的体外和体内疾病模型的结核病，并确定组合的目标，引发最佳的抗结核效果，这是最有可能在临床上的价值。此外，我们还将研究抑制剂组合在减少新的耐药性出现方面的潜力，从而可能延长任何新的治疗方案的寿命。由此产生的信息将为药物发现和开发计划提供信息和帮助，这些计划旨在识别呼吸链组分的抑制剂，当一起使用时，应该有助于对耐多药结核病的新药物治疗方案的杀菌活性，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项目包括我们自己的项目和我们的工业合作伙伴的项目;此外，我们预计所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项目。

项目成果

A Quantitative Method for the Study of HIV-1 and Mycobacterium tuberculosis Coinfection.

• DOI: 10.1093/infdis/jiac491
• 发表时间: 2023-03-01
• 期刊: The Journal of infectious diseases

Antimicrobial Therapies - Methods and Protocols

抗菌疗法 - 方法和方案

• DOI: 10.1007/978-1-0716-1358-0_23
• 发表时间: 2021
• 作者: Donnellan S

SARS-CoV-2 infects an upper airway model derived from induced pluripotent stem cells.

• DOI: 10.1002/stem.3422
• 发表时间: 2021-10
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Djidrovski I;Georgiou M;Hughes GL;Patterson EI;Casas-Sanchez A;Pennington SH;Biagini GA;Moya-Molina M;van den Bor J;Smit MJ;Chung G;Lako M;Armstrong L
• 通讯作者: Armstrong L

Attaching protein-adsorbing silica particles to the surface of cotton substrates for bioaerosol capture including SARS-CoV-2.

• DOI: 10.1038/s41467-023-40696-x
• 发表时间: 2023-08-18
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Collings, Kieran;Boisdon, Cedric;Sham, Tung-Ting;Skinley, Kevin;Oh, Hyun-Kyung;Prince, Tessa;Ahmed, Adham;Pennington, Shaun H.;Brownridge, Philip J.;Edwards, Thomas;Biagini, Giancarlo A.;Eyers, Claire E.;Lamb, Amanda;Myers, Peter;Maher, Simon
• 通讯作者: Maher, Simon

An optimised method for the recovery of laboratory generated SARS-CoV-2 aerosols by plaque assay

• DOI: 10.1101/2022.10.31.514483
• 发表时间: 2022-11
• 期刊: bioRxiv
• 作者: R. Byrne;S. Gould;T. Edwards;D. Wooding;B. Atkinson;Ginny Moore;Kieran Collings;C. Boisdon;S. Maher;G. Biagini;E. Adams;T. Fletcher;S. Pennington