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

抗生素耐药性（AMR）是全球战略重点，并位于英国政府的国家风险登记册中。仅在2019年，估计就有495万例死亡与细菌AMR有关。尽管全球药物研发（R&D）支出继续逐年增加，但抗菌药物发现研究目前并不是一项有吸引力的商业投资。这产生了两个主要后果：这一领域的研发人力资本持续下降，以及治疗有效的抗生素和其他抗菌剂的供应长期下降。迫切需要培训该领域的下一代领导人，并采用创新方法来解决新疗法的耐药性问题，我们的目标是解决这两个问题。BicycleTx拥有一系列研究领域，使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。这种跨部门的方法使公司处于一个罕见的位置，致力于一些重要的活动，以寻找有效的抗菌剂，以及通常更有利可图的治疗领域，这是令人钦佩的。沃里克研究人员在开发新的生化试剂，测定，结构和机械洞察细菌细胞壁（肽聚糖）生物合成的能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合作，并有额外的预约，可以研究整个生物化学途径，从计算机模型，到原子分辨率，再到单分子和单细胞分辨率。在过去的一年里，这开辟了新的调查工具、技术和途径。我们最常用的抗生素靶向肽聚糖生物合成，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，通常通过获得催化抗生素破坏的酶或通过突变改变抗生素的靶点而产生耐药性。回避这种耐药机制的新分子对未来的发展非常重要。沃里克大学和BicycleTx的研究人员之间的学术行业合作伙伴关系将建立在现有的五年合作关系的基础上，以加强英国的生命科学研究环境，并解决AMR这一巨大的医疗挑战。这种伙伴关系所创造的环境将提供培训、使能工具和技术，这些工具和技术已经从现有关系中到位，通过技术准备水平TRL 2-4取得进展，同时提供探索新的更高风险调查途径的自由，这将需要从基础研究TRL 1中开发新的目标和方法，这可能成为未来发展的基础。包括更好地将Bicycles靶向于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灭的革兰氏阴性菌中，以及进入细菌细胞质并开辟更多靶点的能力。我们将在四个工作包中实现这一目标1：扩展对现有双环青霉素结合蛋白抑制剂的机制理解2：鉴定新的双环抑制剂，以达到参与细菌细胞壁产生和维持细菌活力的其他治疗靶点。将这些添加到WP 1 3：设计下一代分子的计算建模，以使Bicycle能够递送到细菌的周质和细胞质中并避免突变抗性的可能性4：结合WP 2和WP 3的产出，生产新型原型抗菌剂。此外，我们现有的合作伙伴关系和AMR行业的更广泛关系将促进简化的工作关系和交付预期，同时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.