Assessing the relevance of Galleria mellonella to antibiotic drug discovery for pulmonary infections

正如我们都日益意识到的那样，由于细菌对通常用于治疗这类感染的抗生素具有耐药性的病例增加，世界面临着细菌感染的新威胁。正在进行的应对这一威胁的努力范围广泛，但有两个关键因素是：1)发现新型抗生素；2)了解细菌如何适应抗生素和防腐剂，以便设计和制定适当的反应。伦敦国王学院的药物科学研究所是这两个领域研究活动的中心。与英国公共卫生国家感染服务中心和其他合作伙伴一起，我们已经确定了四种新型抗生素，它们有可能有效对抗目前引起患者感染的最令人不安的抗生素耐药细菌。我们还采取措施了解这些细菌是如何适应医院使用的防腐剂的。我们已经证明了这是可能发生的，但不知道它是否会发生，也没有发现细菌对防腐剂的适应是否会使细菌变得更强或更弱。将这项研究从实验室转移到临床的关键步骤是建立有效的感染模型，这样我们就可以测试你的抗生素是否可能对病人起作用，或者知道如果细菌适应了防腐剂，感染是否可能更严重或更不严重。通常情况下，这项工作将在老鼠身上进行，我们已经尝试和测试了细菌肺部感染的模型，这些模型模拟了病人在医院通风时可能受到的感染。来自这些模型的数据被广泛认为是可靠的，与人类和其他哺乳动物感染相关（因此它们也适用于兽医科学）。然而，这些模型价格昂贵，需要训练有素的工作人员，并且它们用于筛选许多化合物/条件是不合适的。因此，在两个研究领域都存在瓶颈，并且迫切需要一种道德，成本效益和可预测的替代方案，即使不是专门从事动物研究的实验室也可以使用。其他地方的一些研究小组已经用大蜡蛾的毛虫来代替老鼠进行细菌感染的实验。尽管许多人更愿意使用毛毛虫而不是老鼠或其他动物进行研究，但毛虫当然没有肺，因此人们认为这种模型可能与人类（或宠物或牲畜）的肺部感染无关。尽管如此，一些早期的毛毛虫测试看起来很有希望，并且产生了一些兴奋，毛虫确实是一个合适的模型，可以减少在老鼠身上的测试。然而，一个进一步的问题出现了：通常肺部感染的最大问题细菌对毛虫来说毒性太大，而这些关键细菌的感染模型并不是真正有用的。这个项目的目的是打破这些被认为和现实的障碍，采用毛虫感染模型。我们将使用从埃克塞特大学分拆出来的一家新公司提供的特殊研究等级的卡特彼勒，该公司有望给出更可靠的结果。在国王学院建立这项技术的同时，我们将通过改变细菌的生长方式来适应我们的目的，并使细菌习惯于在毛虫宿主体内生活。当我们做到这一点时，我们将作为一个中心，与我们的合作伙伴和世界各地的其他研究人员分享我们的专业知识。

As we are all increasingly aware, the world faces the renewed threat of bacterial infections due to the rise in cases where bacteria are resistant to the antibiotics that are normally used to treat such infections. Ongoing efforts to counter this threat are wide-ranging but two key elements are: 1) the discovery of new classes of antibiotic and; 2) the understanding how bacteria adapt to both antibiotics and antiseptics so that appropriate responses can be devised and enacted.The Institute of Pharmaceutical Science at King's College London is a hub of research activity in these two areas. Together with the National Infection Service of Public Health England and other partners, we have identified four new classes of antibiotic that have the potential to be effective against the most troubling, antibiotic resistant bacteria currently causing infections in patients. We have also taken steps to understand how these same bacteria adapt to antiseptics that are used in hospitals. We have shown that this can happen, but not whether it does and have not yet discovered if bacterial adaptation to antiseptics makes the bacteria tougher or weaker.The key steps in moving this research from bench to bedside is to have effective infection models so we can test if your antibiotics are likely to work in patients or know if infections are likely to be more or less severe if bacteria adapt to antiseptics. Normally this work would be done in mice and we have tried and tested models of bacterial lung infection which simulate the kind of infections patients might get e.g. when ventilated in hospital.Data from these models is widely regarded as robust and relevant to both human and other mammalian infections (hence they also have application in veterinary science). However, these models are expensive, require highly trained staff and their use for screening many compounds/conditions is inappropriate. Consequently there is a bottleneck in both research areas and an ethical, cost effective and predictive alternative that can be used even by laboratories that do not specialise in animal studies is highly desired.Caterpillars of the greater wax moth have been used by some groups elsewhere to replace mice in models of bacterial infection. Although many people are much more comfortable with the use of caterpillars for research rather than mice or other animals, of course caterpillars do not have lungs and so there is a perception that this model may not be relevant to lung infections in humans (or pets or livestock). Nevertheless, some early tests with caterpillars looked promising and have generated some excitement that caterpillars are indeed an appropriate model that can reduce testing in mice. However a further problem has arisen: often the bacteria that are the biggest problem in lung infections were too toxic to the caterpillars and the infection model for these key bacteria was not really useful.This project aims to break down these perceived and real barriers to adoption of the caterpillar infection model. We will use a special research grade of caterpillar provided by a new company spun-out from Exeter University which is expected to give more reliable results. While establishing this technology at King's we will adapt it for our purposes by modifying how we grow bacteria and also getting bacteria accustomed to living in the caterpillar host. When we have done this we will act as a hub to share our know-how with our partners and other researchers worldwide.