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MICA: Host-directed therapeutics to combat bacterial infections

MICA：对抗细菌感染的宿主导向疗法

基本信息

批准号：
MR/R005893/1
负责人：
Jose Bengoechea
金额：
$ 36.41万
依托单位：
Queen's University Belfast
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR005893%2F1
关键词：
MICA Host directed therapeutics combat

项目摘要

The control of bacterial infections is perhaps the most important achievement of modern medicine. However, the rapid emergence and spread of antibiotic resistance is fast becoming one of the major scientific and health issues of modern times. According to the "National Risk Register of Civil Emergencies", more than 80,000 deaths are estimated in the UK if there is a widespread outbreak of a resistant microbe. The development of new antibiotics is slow and difficult work but bacterial resistance is decreasing our arsenal of existing drugs. A post-antibiotic era - in which common infections and minor injuries can kill - far from being an apocalyptic fantasy, is a very real possibility for the 21st Century. The O'Neill review on antibiotic resistance sets out the global threat by highlighting that "drug-resistant infections already kill hundreds of thousands a year globally, and by 2050 that figure could be more than 10 million". Of particular concern is the mounting prevalence of infections caused by multidrug resistant (MDR) Gram-negative bacteria, in particular Klebsiella pneumoniae. This pathogen has been singled out as an "urgent threat to human health" by the UK Government, the U.S. Centers for Disease Control and Prevention, and the World Health Organization due to extremely drug resistant strains. In 2014, the percentage of MDR K. pneumoniae isolates was above 10% in more than half of all reporting European countries, including the UK. K. pneumoniae infections are particularly a problem among neonates, elderly and immunocompromised individuals within the healthcare setting, but this organism is also responsible for a significant number of community-acquired infections including pneumonia and sepsis. Very few therapeutic options are left for patients infected with MDR K. pneumoniae with additional resistance to carbapenems, and are often limited to combination therapy and to colistin. Alarmingly, recent studies have recognised that several K. pneumoniae virulent and MDR clones have access to a mobile pool of virulence and antimicrobial resistance genes; hence making possible the emergence of a MDR, hypervirulent K. pneumoniae clone capable of causing untreatable infections in healthy individuals. K. pneumoniae is exemplary of the mismatch between unmet medical needs and the current antimicrobial development pipeline. Therefore, it is an urgent priority to develop effective therapeutics based on new targets and concepts. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of MDR Klebsiella infections. Rising to this health challenge, and by capitalizing on a decade of studies on K. pneumoniae infection biology of the Bengoechea laboratory, in this project we will provide solid pre-clinical evidence demonstrating that inhibition of a host protein (Src kinase) targeted by Klebsiella to ablate our defences will influence decisively the outcome of host-Klebsiella interaction thereby limiting pathogen survival. By teaming up with AstraZeneca, we will demonstrate that treatment with a company proprietary Src kinase inhibitor will favour pathogen clearance. The proven excellent safety, and tolerability of the Src inhibitor may anticipate a fast-track transition from the pre-clinical stage to further clinical clinical development hence bypassing several initial hurdles of the drug development process. Altogether, we envision that our results will encourage other academics as well as other pharmaceutical companies to follow this avenue of research to tackle the problem of lack of therapies for microbes resistant to antibiotics.

控制细菌感染也许是现代医学最重要的成就。然而，抗生素耐药性的迅速出现和传播正在迅速成为现代主要的科学和健康问题之一。根据“国家民事紧急情况风险登记册”，如果抗药性微生物大范围爆发，估计英国将有8万多人死亡。新抗生素的开发是缓慢而困难的工作，但细菌耐药性正在减少我们现有的药物库。后抗生素时代--普通感染和轻微伤害都可能致命--远非世界末日的幻想，而是21世纪非常真实的可能性。奥尼尔关于抗生素耐药性的评论通过强调“耐药感染每年已经在全球范围内杀死数十万人，到2050年这一数字可能超过1000万”来阐述全球威胁。特别值得关注的是，由多重耐药（MDR）革兰氏阴性菌，特别是肺炎克雷伯氏菌引起的感染的患病率不断上升。这种病原体已被英国政府、美国疾病控制和预防中心和世界卫生组织列为“对人类健康的紧迫威胁”，因为它具有极强的耐药性。2014年，MDR K.在超过一半的报告欧洲国家，包括英国，肺炎分离株高于10%。K.肺炎感染在新生儿、老年人和健康护理环境中的免疫功能低下的个体中尤其是一个问题，但这种生物体也是大量社区获得性感染（包括肺炎和败血症）的原因。感染MDR K的患者几乎没有治疗选择。此外，肺炎链球菌还对碳青霉烯类具有额外的耐药性，并且通常限于联合治疗和粘菌素。令人担忧的是，最近的研究已经认识到，一些K。肺炎克雷伯氏菌的毒力和MDR克隆可以进入一个移动的毒力和抗微生物药物抗性基因库，因此可能出现MDR、超毒力克雷伯氏菌。能够在健康个体中引起不可治疗的感染的肺炎克隆。K.肺炎是未满足的医疗需求与当前抗微生物开发管道之间不匹配的示例。因此，基于新的靶点和概念开发有效的治疗方法是当务之急。不幸的是，目前，我们不能确定候选化合物在后期开发用于治疗MDR克雷伯氏菌感染。面对这一健康挑战，通过利用十年来对K。在本戈切亚实验室的肺炎感染生物学中，在该项目中，我们将提供可靠的临床前证据，证明抑制克雷伯氏菌靶向的宿主蛋白（Src激酶）以消除我们的防御将决定性地影响宿主-克雷伯氏菌相互作用的结果，从而限制病原体存活。通过与阿斯利康的合作，我们将证明使用公司专有的Src激酶抑制剂治疗将有利于病原体清除。Src抑制剂已被证明具有优异的安全性和耐受性，可以预期从临床前阶段到进一步临床开发的快速过渡，从而绕过药物开发过程的几个初始障碍。总而言之，我们设想我们的结果将鼓励其他学者以及其他制药公司遵循这一研究途径，以解决缺乏对抗生素耐药的微生物的治疗方法的问题。