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Harnessing natural product diversity to combat multidrug-resistant pathogens

利用天然产物多样性对抗多重耐药病原体

基本信息

批准号：
MC_PC_MR/T029579/1
负责人：
Mathew Upton
金额：
$ 162.84万
依托单位：
Plymouth University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MC_PC_MR%2FT029579%2F1
关键词：
Harnessing natural product diversity combat

项目摘要

Antimicrobial resistance (AMR) constitutes one of the greatest threats to global public health. The leading AMR threats in South Africa (SA) reflect those on the WHO list of Critical/High Priority pathogens, which includes Gram-negative ESKAPE organisms, with growing levels of resistance to carbapenems and colistin. There is increasing concern over Sexually Transmitted Infections caused by resistant Neisseria gonorrhoea. There is a clear, unmet need for new agents to combat these bacterial pathogens. We will build on the extensive repertoire of SA and UK drug discovery expertise, with the aim of unlocking the potential resources contained in natural marine and terrestrial biota. In this work, we will have a strong emphasis on samples from SA, which is the 3rd most bio-diverse natural habitat on Earth and has the potential to deliver key natural product (NP)-derived antibiotics that are new to science and able to help meet the need for new antibiotics.NPs are an unprecedented starting point for antibiotic discovery; NPs and their synthetic analogues are the sources of >80% of all clinically-utilised antibiotics. They represent the only validated source of chemical diversity capable of delivering a sustained pipeline of novel antibacterial drug candidates.Our project consortium is a complementary, multi-disciplinary and balanced team of international experts in clinical/medical microbiology, natural product discovery, medicinal chemistry, antibiotic evaluation, biophysical analysis, bioinformatics, metagenomics, in silico discovery and molecular biology. Team members have successfully delivered multi-partner, multi-national research programmes and there are already established collaborations between SA and the UK within our group. Working together on this project will strengthen the current collaborations, forge new long-term relationships and further develop AMR drug discovery by building capacity for future research to explore the NP diversity in samples from SA and other locations and provide an on-going supply chain of new antibiotic leads.In the integrated research projects proposed in this Hub, we will deploy new approaches for NP discovery, with an emphasis on samples selected from the highly diverse SA terrestrial and marine biota, which has yet to be systematically screened for antibacterial compounds. We will examine NP extract libraries that have not been mined for antibiotic candidates and we will also explore the hidden potential of microbes by mining metagenomic datasets and the genomes of cultured isolates. This approach will overcome many of the previous limitations of NP discovery, mitigating risks to maximise the potential for delivery of new antibiotic candidate hits.We will conduct exchange visits for post doctoral researchers in both directions between SA and the UK and we will deliver a series of training workshops in both countries for PhD students and early career researchers. This will include training in basic sample collection and antimicrobial discovery methods, through to specialist training in NP characterisation and analysis tools, bioinformatics, lead optimisation, preliminary in vivo evaluation, PK/PD and entrepreneurship.Our integrated programme of research and training across the UK and SA will draw on our expertise and access to diverse resources across our transnational network. Through the Hub activities, we will establish new infrastructure, expanding cutting-edge research capacity and we will comprehensively rejuvenate the discovery of novel antibiotics from NP sources.

抗菌素耐药性（AMR）是全球公共卫生面临的最大威胁之一。南非的主要抗菌素耐药性威胁反映了世卫组织关键/高优先级病原体清单上的威胁，其中包括革兰氏阴性ESKAPE生物，它们对碳青霉烯类和粘菌素的耐药性水平不断提高。对耐药淋病奈瑟菌引起的性传播感染的关注日益增加。对对抗这些细菌病原体的新药剂的需求显然尚未得到满足。我们将以南非和英国的药物发现专业知识为基础，以解锁天然海洋和陆地生物群中包含的潜在资源为目标。在这项工作中，我们将重点关注来自SA的样本，SA是地球上生物多样性排名第三的自然栖息地，具有提供关键天然产物（NP）衍生抗生素的潜力，这些抗生素对科学来说是新的，能够帮助满足新抗生素的需求。NPs是抗生素发现的一个前所未有的起点；NPs及其合成类似物是所有临床使用抗生素的80%的来源。它们代表了唯一经过验证的化学多样性来源，能够提供持续的新型抗菌候选药物管道。我们的项目联盟是一个互补的、多学科的、平衡的团队，由临床/医学微生物学、天然产物发现、药物化学、抗生素评估、生物物理分析、生物信息学、宏基因组学、硅发现和分子生物学等领域的国际专家组成。团队成员已经成功地交付了多合作伙伴，多国研究项目，并且已经在我们集团内建立了SA和英国之间的合作关系。在这个项目上的共同努力将加强目前的合作，建立新的长期关系，并通过建立未来研究的能力来进一步发展抗菌素耐药性药物的发现，以探索来自南非和其他地区的样品中的NP多样性，并提供持续的新抗生素线索供应链。在该中心提出的综合研究项目中，我们将部署新的NP发现方法，重点是从高度多样化的SA陆地和海洋生物群中选择的样品，这些样品尚未系统地筛选抗菌化合物。我们将研究尚未挖掘抗生素候选物的NP提取物文库，我们还将通过挖掘宏基因组数据集和培养分离株的基因组来探索微生物的隐藏潜力。这种方法将克服以前NP发现的许多限制，降低风险，最大限度地提高新的候选抗生素的潜力。我们将在SA和英国之间进行博士后互访，并在两国为博士生和早期职业研究人员举办一系列培训研讨会。这将包括基本样本收集和抗菌药物发现方法的培训，以及NP表征和分析工具、生物信息学、先导物优化、初步体内评估、PK/PD和创业方面的专业培训。我们在英国和南非的综合研究和培训计划将利用我们的专业知识，并通过我们的跨国网络获取各种资源。通过中心活动，我们将建立新的基础设施，扩大尖端研究能力，并将全面振兴从NP来源发现新型抗生素。