The chemical origins of biological interactions: an evolutionarily refined approach for natural products discovery

我们目前面临的最大挑战之一是人类病原体对抗生素的耐药性的发展。过去，科学家从土壤中发现的微生物中收获了大量的抗菌和抗真菌分子。这些从天然来源分离出来的分子被称为天然产物。由于许多天然产物的结构复杂，它们往往具有有用的生物活性。事实上，天然产物的结构为大多数成功的候选药物提供了灵感。然而，制药行业和学术界都认识到，使用标准程序(如分离土壤微生物)寻找天然产物是劳动密集型的，而且往往会导致重新发现已知化合物。在这项拟议的研究中，我们将开发新的技术，以更低的成本和更高的成功率从天然来源中鉴定新的生物活性类药物分子。为了实现这一目标，我们将研究从同一生物环境(例如人类肠道、群居昆虫的蜂巢)中分离出来的多种微生物，它们在那里自然生长并相互竞争相同的资源。我们将在实验室里进行一项测试，看看哪些微生物最能成功地杀死从同一来源分离出来的其他微生物，然后确定哪些天然产品对这种杀菌活动负责。这项工作对于提供药物发现和抗生素耐药性研究的新进展极其重要。我们发现的新分子将作为其他化学家合成和修饰的靶标；这些分子也将作为药物先导，供生物化学家、微生物学家和药剂学家进一步测试和探索。如果我们的新天然产品显示出良好的生物活性，我们将在进行商业开发之前为这些化合物申请专利。这项研究的预期结果不仅将促进加拿大科学界的发展，也将促进其经济利益。成功地将任何新的天然产品开发成可使用的药物将产生全球影响，并最终使普通公众受益。

One of the greatest challenges we currently face is the development of antibiotic-resistance in human pathogens. In the past, scientists have harvested a large number of antibacterial and antifungal molecules from microbes found in the soil. These molecules that are isolated from natural sources are referred to as natural products. Because many natural products are structurally complex, they often have useful bioactive properties. Indeed, the structures of natural products form the inspiration for the majority of successful drug candidates. However, both the pharmaceutical industry and academia have realized that searching for natural products using standard procedures (e.g. isolating soil microbes) is labour-intensive and often leads to rediscovery of known compounds.******In this proposed research, we will develop novel techniques to identify new biologically-active drug-like molecules from natural sources at a lower cost and higher success rate. To achieve this goal, we will study multiple microbes isolated from the same biological environment (e.g. the human gut, the hives of social insects) where they have naturally grown and been in competition with each other for the same resources. We will develop a test in the lab to see which microbes can most successfully kill off other microbes isolated from the same source, and then determine which natural products are responsible for this killing activity.******This work is extremely important for providing new developments in drug discovery and antibiotics resistance research. The new molecules we find will serve as targets for other chemists to synthesize and modify; the molecules will also serve as drug leads for biochemists, microbiologists and pharmacologists to further test and explore. If our new natural products show promising biological activity, we will patent the compounds before pursuing commercial development. The anticipated outcomes of this research would promote not only the scientific community of Canada, but also its economic interests. Successful development of any new natural products into usable drugs would have a global impact and ultimately benefit the general public.