MICA: Host-directed therapeutics to combat bacterial infections

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蔓延正迅速成为现代主要的科学和健康问题之一。根据“国家突发民事事件风险登记册”，如果一种耐药微生物广泛爆发，估计英国将有8万多人死亡。新抗生素的开发是一项缓慢而艰巨的工作，但细菌耐药性正在减少我们现有药物的数量。后抗生素时代——常见的感染和轻微的伤害都可能导致死亡——远不是世界末日的幻想，而是21世纪非常有可能出现的现实。O'Neill关于抗生素耐药性的评论强调指出，“耐药性感染已经在全球每年造成数十万人死亡，到2050年，这一数字可能超过1000万”，从而提出了全球威胁。特别令人关切的是，由耐多药革兰氏阴性菌，特别是肺炎克雷伯菌引起的感染日益流行。这种病原体被英国政府、美国疾病控制和预防中心以及世界卫生组织列为“对人类健康的紧急威胁”，原因是其菌株具有极强的耐药性。2014年，在包括英国在内的半数以上有报告的欧洲国家中，耐多药肺炎克雷伯菌分离株的比例超过10%。肺炎克雷伯菌感染在新生儿、老年人和医疗保健机构免疫功能低下的个体中尤其是个问题，但这种微生物也导致大量社区获得性感染，包括肺炎和败血症。对碳青霉烯类具有额外耐药性的耐多药肺炎克雷伯菌感染患者的治疗选择很少，通常仅限于联合治疗和粘菌素。令人震惊的是，最近的研究已经认识到，一些肺炎克雷伯菌毒力和耐多药克隆可以进入毒力和抗微生物药物耐药性基因的流动库；因此，有可能出现耐多药、高毒力肺炎克雷伯菌克隆，能够在健康个体中引起无法治疗的感染。肺炎克雷伯菌是未满足的医疗需求与当前抗菌药物开发管道之间不匹配的典型例子。因此，开发基于新靶点和新概念的有效治疗方法是当务之急。不幸的是，目前，我们还不能确定治疗耐多药克雷伯菌感染的晚期候选化合物。为了应对这一健康挑战，并利用Bengoechea实验室十年来对肺炎克雷伯菌感染生物学的研究，在本项目中，我们将提供坚实的临床前证据，证明克雷伯菌靶向宿主蛋白（Src激酶）的抑制作用将决定性地影响宿主-克雷伯菌相互作用的结果，从而限制病原体的存活。通过与阿斯利康合作，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良好的安全性和耐受性，这可能预示着从临床前阶段到进一步临床临床开发的快速过渡，从而绕过药物开发过程中的几个最初障碍。总之，我们设想我们的结果将鼓励其他学术界和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微生物治疗的问题。

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.