High-throughput discovery of novel antibiotics against nontuberculous mycobacteria

非结核分枝杆菌(NTM)是一组每年导致100,000多例致命肺部感染的细菌。感染主要影响免疫功能低下的患者和囊性纤维化(CF)社区，囊性纤维化患者中有10%受到感染。高度的内在抗菌素耐药性和持续的感染使这些病原体变得难以治疗，而且往往无法治疗。目前的NTM治疗方案包括密集的多种药物方案，疗效低，副作用严重，治疗负担高。平均治疗成本在GB 4k-GB 16k/年之间，额外的医疗费用高达10k GB。随着耐药率的增加，以及在过去40年中没有新的抗生素类别进入市场，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的所有抗生素和5种主要类别中的4种来自~1%的土壤微生物，这些微生物很容易在实验室进行培养。这种生物资源现在已经耗尽在新型抗生素上，而发现新的合成解决方案的努力未能填补这一空白，事实证明开发成本高昂(每种新型抗生素10亿英镑)。获得剩余99%的未培养微生物是发现新抗生素的最佳机会。BactoBio开发了一个结合合成生物学、下一代测序和机器学习的平台来培养以前无法培养的微生物。到目前为止，我们已经获得了1800个物种的独家访问权。在这个项目中，我们将扩大和筛选我们内部的独特微生物种子库，以生产针对非传染性支气管炎的新型抗生素。我们已经制定了一个雄心勃勃的目标，要找到3个针对NTM的有前景的抗生素化合物候选化合物，从而为制药业的进一步投资提供了一个令人信服的理由，通过每种化合物价值1亿GB的许可交易。

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.