Antimicrobial Resistance: Breakthrough Compound Discovery through Mechanistic Studies combined with Bicycle Technology and Target Validation

抗菌素耐药性(AMR)是一项全球战略优先事项，位于英国政府的国家风险登记册中。仅在2019年，估计就有495万人死于细菌AMR。尽管全球药物研发(R&D)支出持续逐年增加，但抗菌药物发现的研究目前并不是一个有吸引力的商业投资。这造成了两个主要后果：用于该领域研发的人力资本持续下降，以及从长远来看，治疗有效的抗生素和其他抗菌剂的可获得性下降。我们迫切需要培训该领域的下一代领导力，以及用新的疗法来应对耐药性的创新方法，我们的目标是同时解决这两个问题。BicycleTx拥有一系列研究领域，利用独特的技术平台提供高质量的双环肽作为潜在的治疗药物。这种横断式的方法使该公司处于罕见的地位，能够在通常更有利可图的治疗领域之外从事一些重要的活动来寻找有效的抗菌剂，这是令人钦佩的。华威的研究人员在开发新的生化试剂、分析、对细菌细胞壁(肽聚糖)生物合成的结构和机械洞察力方面享有国际声誉。最近，该团队与一座拥有最先进设施的新建筑共处一室，并进行了额外的预约，该团队可以跨尺度研究整个生化途径，从硅胶模型到原子拆分到单分子和单细胞拆分。在过去的一年里，这为调查开辟了新的工具、技术和途径。我们最常用的抗生素是针对肽聚糖的生物合成，其中许多是天然产物，如青霉素和更广泛的β-内酰胺抗生素家族，它们已经产生抗药性，通常是通过获得催化破坏抗生素的酶或通过突变改变抗生素的靶标而产生的。避开这种抗性机制的新分子对未来的发展非常重要。华威大学的研究人员和BicycleTx公司的这一学术行业合作伙伴关系将建立在现有的五年关系的基础上，以加强英国的生命科学研究环境，并应对AMR这一巨大的医疗挑战。这一伙伴关系创造的环境将提供培训，使现有工具和技术从现有关系发展到技术准备水平TRL2-4，同时提供探索新的高风险调查途径的自由，这将需要从基础研究TRL1开发新的目标和方法，这可能成为未来发展的基础，包括更好地针对自行车与世卫组织优先病原体的青霉素结合蛋白的能力，包括更好地渗透到难以杀死的革兰氏阴性细菌，我们将通过四个工作包来实现这一点：1：扩展对现有自行车青霉素结合蛋白抑制剂的机理了解2：识别新的自行车抑制剂，以增加与细菌细胞壁生产和维持细菌生存相关的治疗靶点。将这些添加到WP1 3：设计下一代分子的计算模型，以使自行车能够输送到细菌的周质和细胞质中，并避免突变耐药性的可能性4：将WP2和WP3的输出结合起来，以产生新型原型抗菌剂。此外，我们现有的合作伙伴关系和AMR部门更广泛的关系将促进精简的工作关系和交付的预期，以及为下一代研究领导者提供独特的培训环境。

Antimicrobial resistance (AMR) is a global strategic priority and sits within the UK Government's National Risk Register. In 2019 alone, there were an estimated 4.95 million deaths associated with bacterial AMR. Although global pharmaceutical research and development (R&D) spend continues to increase year on year, research into antimicrobial drug discovery is not currently an attractive commercial investment. This has had two major consequences: an ongoing decline of human capital for R&D in this field, and a decline over the longer term in availability of therapeutically effective antibiotics and other antimicrobial agents. Both training the next generation of leadership in the field and innovative approaches to tackle resistance with new therapeutics are urgently required, we aim to tackle both. BicycleTx has a portfolio of research areas that uses a unique technology platform to deliver high quality bi-cyclic peptides as potential therapeutics. This cross-sectional approach places the company in a rare position to commit some significant activity to search for effective antimicrobials alongside therapeutic areas that are typically more profitable, this is admirable.Warwick researchers have international reputation in their ability to develop new biochemical reagents, assays, structural and mechanistic insight into bacterial cell wall (peptidoglycan) biosynthesis. Recently co-located into a new building with state of the art facilities with additional appointments this team can study the whole biochemical pathway across scale, from models in silico, through atomic resolution to single molecules and single cell resolution. In the past year this opened up new tools, techniques and avenues of investigation. Our mostly commonly used antibiotics target peptidoglycan biosynthesis, many of these are natural products, such as penicillins and the wider family of beta-lactam antibiotics, to which resistance has developed, typically by the acquisition of enzymes that catalyse the destruction of the antibiotic or by mutation altering the target of the antibiotic. New molecules that sidestep such resistance mechanisms are really important for future developments.This academic industry partnership between researchers at the University of Warwick and BicycleTx will build upon an existing five year relationship to strengthen the Uk's life science research environment and address the great healthcare challenge which is AMR. The environment created by this partnership will provide training, enabling tools and technologies already in place from the existing relationship to progress through technology readiness levels TRL 2-4 while providing the freedom to explore new higher risk avenues of investigation that will require new targets and methods to be developed from basic research,TRL1, that may become the basis for future development, including the ability to better target Bicycles to penicillin binding proteins of WHO priority pathogens, including better permeation into difficult to kill gram negative bacteria, and access the bacterial cytoplasm and open up still further targets.We will deliver this in four work packages1: Extending the mechanistic understanding of existing Bicycle Penicillin Binding Protein inhibitors 2: Identification of new Bicycle inhibitors to additional therapeutic targets involved in bacterial cell wall production & maintaining bacterial viability. Adding these into WP1 3: Computational modelling to design next generation molecules to enable Bicycle delivery into the periplasm and cytoplasm of bacteria and evasion of the potential for mutational resistance 4: Combining outputs from WP2 and WP3 to generate novel prototypical antimicrobial agents.Additionally our existing partnership and wider relationships across the AMR sector will facilitate a streamlined working relationship and expectations of delivery, alongside a unique training environment for the next generation of research leaders.