High-throughput discovery of novel antibiotics against nontuberculous mycobacteria

非结核分枝杆菌（NTM）是一组每年造成超过100,000例致命肺部感染的细菌。感染主要影响免疫功能低下患者和囊性纤维化（CF）群体。10%的CF患者感染。高水平的内在抗菌素耐药性和持续感染使这些病原体难以治疗，而且往往无法治疗。目前的NTM治疗方案包括疗效低、副作用严重和治疗负担高的强化多药方案。平均治疗费用在每年4万至1.6万英镑之间，额外的医疗保健支出高达1万英镑。由于耐药率不断上升，而且在过去40年中没有新的抗生素类别进入市场，因此迫切需要新的抗生素治疗方案来对抗NTM感染。该项目旨在改善英国和全球NTM患者的临床前景、预期寿命和生活质量。目前用于治疗NTM的所有抗生素中有80%和5大类抗生素中的4类都来自可在实验室中轻松培养的约1%的土壤微生物。这种生物资源现在已经被新型抗生素耗尽，而发现新的合成解决方案的努力未能填补这一空白，并且开发成本高昂(？每个新型抗生素10亿英镑)。接近剩余99%的未培养微生物是发现新抗生素的最佳机会。Bactobio开发了一个平台，结合了合成生物学，下一代测序和机器学习来培养以前不可培养的微生物。到目前为止，我们已经获得了？1800个物种。在这个项目中，我们将扩大和筛选我们内部的独特微生物物种库，用于生产针对NTM的新型抗生素。我们设定了一个雄心勃勃的目标，即找到3种有前景的针对NTM的抗生素候选化合物，从而为制药行业提供一个令人信服的案例，通过价值10美元的许可交易进一步投资。每个化合物价值1亿英镑。

Nontuberculous mycobacteria(NTM) are a group of bacteria responsible for over 100,000 deadly lung infections annually. Infections predominantly impact immunocompromised patients and the cystic fibrosis(CF) community, with ?10% of people with CF infected. High levels of intrinsic antimicrobial resistance and persistent infections have made these pathogens hard and often impossible to treat.Current NTM therapeutic options involve intensive multi-drug regimens with low efficacy, severe side effects and high treatment burden. Average treatment costs range between £4k-£16k/year with additional healthcare spend of up to £10k. With increasing rates of resistance and no new antibiotic classes entering the market in the last 40 years, there is an urgent need for new antibiotic treatment options to combat NTM infections. The project aims to improve the clinical outlook, life expectancy and quality of life of NTM patients in the UK and globally.80% of all antibiotics and 4 of 5 major classes used to treat NTM today derive from the ~1% of soil microbes which can be readily cultured in the laboratory. This bioresource has now been exhausted for novel antibiotics whilst efforts to discover new synthetic solutions have failed to fill the gap and have proven costly to develop(?£1Bn per novel antibiotic). Accessing the remaining 99% of uncultured microbes represents the best opportunity to discover new antibiotics.Bactobio has developed a platform that combines synthetic biology, next-generation sequencing, and machine learning to culture previously unculturable microbes. So far, we have gained exclusive access to ?1,800 species. In this project, we will expand and screen our in-house library of unique microbial species for production of novel antibiotics against NTM. We have set an ambitious goal to find 3 promising antibiotic chemical compound candidates targeting NTM, thereby providing a compelling case for further investment from the pharmaceutical industry through licensing deals valued at ?£100Mn per compound.