Developing mechanistic understanding to improve the activity of bicyclic peptides as novel antimicrobials

每年，数百万人死于细菌感染，数千万人遭受这些感染的后果。青霉素药物的发现曾经为治疗这些感染打开了大门。然而，随着时间的推移，细菌已经进化出对这些基本药物的耐药性，使它们无效。例如，当细菌产生一种称为β-内酰胺酶的酶时，对青霉素的耐药性就会发生，这种酶通过在杀死细菌之前分解青霉素来起作用。世界卫生组织总干事将抗生素耐药性称为“缓慢的海啸”。如果不加以控制，许多普通的医疗方法将变得无用，更多的人将死于传染病。需要进行研究以发现新的药物。大多数细菌已经对青霉素产生了抗药性，我们的目标是创造一类新的抑制剂，称为“双环”（双环肽），其作用类似于青霉素，但对β-内酰胺酶不敏感。自行车在化学上与青霉素非常不同，是在英国一家中型制药公司BicycleTx使用专有的“噬菌体展示”技术发现的。这笔赠款将支持专家研究员，具有相关的专业知识，从沃里克大学与BicycleTx合作，以改善这些自行车的活动。细菌通过细胞壁保护自己免受外界的伤害。如果我们能阻止这种细胞壁的形成，细菌很快就会死亡。青霉素结合蛋白（PBP）是所有细菌用来产生细胞壁的一种特殊蛋白质家族。顾名思义，青霉素可以与PBPs结合，抑制它们的作用，从而阻止细胞壁的形成并杀死细菌。由于PBPs存在于所有种类的细菌中，因此青霉素等药物可用于治疗许多不同的细菌感染，因此被医生广泛使用。自行车也能抑制PBPs，但它们是非常新的，在用于临床之前，它们需要进一步优化。关于它们如何工作的几个重要问题需要回答：-它们如何与PBPs相互作用？-细菌可能使用哪些方法来对自行车产生耐药性？我们如何确保自行车可以进入细菌细胞，以产生对PBPs的影响？为了回答这些问题，需要了解PBPs和一些不同的技术。使用的方法之一是X射线晶体学，它使科学家能够观察蛋白质和自行车的3D原子结构。这些结构可以用来制造具有更强抑菌能力的改进型自行车。如果细菌在实验室中与自行车一起生长，它们会慢慢进化出耐药性。然后，自行车可以在临床环境中发生相同进化的预期中进行修改。为了研究自行车如何进入细菌细胞，我们可以使用BicycleTx开发的一种新测试。不同的自行车将被设计并测试其穿透细菌细胞的能力。沃里克大学和借调人员拥有与这些研究领域高度相关的专业知识，了解青霉素如何与PBPs相互作用，并开发新的方法来研究这一点，以及新的抑制剂如自行车可能如何起作用。通过将知识转移到BicycleTx，我们可以加速自行车的发展。该项目解决了全球对有效新型抗生素的需求，以应对日益严重的抗菌素耐药性威胁。一种新的抗生素将有助于保护医疗系统。该项目还促进了大学和英国制药企业之间的知识交流，这将有助于英国成为该领域的世界领导者。最后，该项目将促进年轻科学家的职业生涯，为他们提供抗生素创新职业生涯的技能，知识和专业网络。

Each year, millions of people die from bacterial infections and tens of millions suffer from the consequences of these infections. The discovery of the drug penicillin once opened the door to treat these infections. However, over time, bacteria have evolved resistance to these essential drugs, making them ineffective. For example, resistance to penicillins can occur when the bacteria produce an enzyme called beta-lactamase that acts by breaking down the penicillin before it kills the bacteria. The World Health Organisation's Director-General has called antimicrobial resistance a "slow tsunami". Left unchecked, many common medical treatments will become useless and many more people will die from infectious diseases. Research is needed to find new drugs. Already, most species of bacteria exhibit resistance to penicillin.Our vision is to create a new class of inhibitors called "Bicycles" (bicyclic peptides), which act similarly to penicillin but are not vulnerable to beta-lactamases. Bicycles are chemically very different to penicillin and were discovered using proprietary "Phage-display" technology at BicycleTx, a medium sized UK pharmaceutical company. This grant will support an expert researcher, with relevant expertise, from the University of Warwick to work with BicycleTx to improve the activity of these Bicycles. Bacteria are protected from the outside world by surrounding themselves with a cell wall. If we can stop this cell wall being made, the bacteria quickly die. Penicillin binding proteins (PBPs) are a family of specialised proteins used by all bacteria to produce the cell wall. As the name suggests, penicillin can bind to PBPs inhibiting their action, thereby preventing cell wall formation and killing the bacteria. Because PBPs are found in all species of bacteria, drugs like penicillin can be used to treat many different bacterial infections and are therefore extensively used by doctors.Bicycles also inhibit PBPs, but they are very new and before they can be used in a clinical setting, they need further optimisation. Several important questions about how they work need to be answered:- How do they interact with PBPs?- What are the methods that bacteria might use to become resistant to Bicycles?- How do we make sure the Bicycles can break into the bacterial cell in order to have their effect on PBPs?To answer these questions, knowledge about PBPs and a number of different techniques are needed. One of the methods used is X-ray crystallography, which allows scientists to observe the 3D, atomic structures of proteins and Bicycles. These structures can be used to make improved versions of Bicycles which have an even stronger ability to inhibit bacteria. If bacteria are grown in the laboratory in the presence of Bicycles, they will slowly evolve resistance. The Bicycle can then be modified in anticipation of the same evolution happening in a clinical setting. To study how well a Bicycle can enter a bacterial cell, we can use a new test developed by BicycleTx. Different Bicycles will be designed and tested for their ability to penetrate bacterial cells.The University of Warwick and the secondee have expertise highly relevant to these fields of study, knowing how penicillin interacts with PBPs and developing new ways to study this and how new inhibitors such a Bicycles might work. By transferring knowledge to BicycleTx, we can accelerate the development of Bicycles.This project addresses the global demand for effective new antibiotics to combat the rising threat of antimicrobial resistance. A new class of antibiotics would help safeguard healthcare systems. The project also boosts the exchange of knowledge between universities and UK pharmaceutical enterprises which will help the UK become a world leader in this field. Finally, the project will boost the career of a young scientist, providing them with the skills, knowledge and professional network for a career in antibiotic innovation.