Identification of new classes of antibiotics based on bicyclic peptides (Bicycles)

“抗生素耐药性是一个重大的公共健康威胁，可能会对医学乃至我们的生活方式产生巨大影响。有报告指出，如果没有实质性的干预措施，到2050年，可能有1亿人死于抗生素耐药性细菌的感染。问题不仅仅是无法治愈的感染导致的死亡，还有在没有有效抗生素的情况下无法进行其他医疗程序，如择期手术、移植和癌症化疗。据估计，经济成本可能为100万亿美元，占世界GDP的2.5%。新抗生素的开发停滞不前，部分原因是经济原因，近年来抗生素开发没有提供足够的投资回报，但也有技术原因，事实证明开发新抗生素极其困难。在开发现有抗生素类别的新成员方面取得了一些成功，但在过去40年中只引入了三种新类别的抗生素。自行车治疗公司开发了一种改变游戏规则的新线索发现技术，该技术已被证明在肿瘤学领域非常有效，并正在与主要制药公司合作开发眼科、呼吸系统、心血管和代谢性疾病。这一平台在新抗生素的开发中具有巨大的应用潜力。由于制药公司的化合物集合不太适合抗菌应用，新抗生素的开发一直是极其困难的。此外，开发新的抗菌药的理想目标是复杂的，与传统的药物发现方法背道而驰。只有经过数百万年进化优化的天然分子才会成功，但事实证明，新的分子越来越难发现。自行车技术使用噬菌体(细菌病毒)来产生和呈现大量的类药物分子，比合成化学所能实现的分子大许多个数量级，并在仍然附着在噬菌体上的情况下测试它们的靶向结合。因此，种群可以通过多个进化周期丰富有希望的线索。这种方法的力量类似于进化中的自然选择，但进行的时间是几个月，而不是数千年。我们的目标是针对抗菌靶标产生这种方法的原则证明数据，如果成功，将建立一家衍生公司，利用这项技术对抗广泛的抗菌靶标。我们认为，这项创新技术在抗菌领域是新的，但在其他地方得到了验证，可能会对抗菌素耐药性问题产生重大影响。“

"Resistance to antibiotics is a major public health threat that could have huge impact on medicine and indeed our way of life. Reports have suggested that without substantial interventions, 100 million people could die from infection from antibiotic-resistant bacteria by 2050\. The issue is not just deaths from untreatable infection but the inability to carry out other medical procedures such as elective surgery, transplantation and cancer chemotherapy without effective antibiotics. It has been estimated that the economic cost could be $100 trillion or 2.5% of World GDP.Development of new antibiotics has stalled partly for economic reasons in that antibiotic development in recent years has not provided a sufficient return on investment, but partly also for technical reasons in that it has proved extremely difficult to develop new antibiotics. Some success has been achieved in developing new members of existing classes of antibiotics, but only three new classes of antibiotics have been introduced in the last 40 years.Bicycle Therapeutics has developed a game-changing new lead discovery technology which has proven extremely productive in the oncology field and is also being exploited in collaboration with major pharmaceutical companies in ophthalmology, respiratory, cardiovascular and metabolic diseases. This platform has tremendous potential for application to development of new antibiotics.Development of new antibiotics has been extremely difficult because the compound collections of pharmaceutical companies are not well-suited to antibacterial applications. Furthermore, the ideal targets for development of new antibacterials are complex and recalcitrant to traditional drug discovery approaches. Only natural molecules optimised over millions of years by evolution have tended to be successful, but new ones are proving harder and harder to find.The Bicycle technology employs bacteriophage (viruses of bacteria) to generate and present drug-like molecules in huge numbers, many orders of magnitude greater than could be achieved by synthetic chemistry, and test them for target binding while still attached to the bacteriophage. The population can therefore be enriched for promising leads through multiple evolutionary cycles.The power of the approach is similar to natural selection in evolution, but conducted over months rather than millennia. Our goal is to generate proof-of-principle data for this approach against antibacterial targets and, if successful, to establish a spin-off company to utilize the technology against a broad range of antibacterial targets. We believe that this innovative technology, new to the antibacterial field but proven elsewhere, could have a major impact on the antimicrobial resistance problem."