Natural Product Discovery from Marine Microbes

天然产品在提供具有广泛应用的新活性成分方面有良好的记录。从历史上看，一个主要的目标领域一直是制药行业。例如，2015年诺贝尔生理学或医学奖共同授予坎贝尔和大村，以表彰他们发现了治疗河盲症的阿维菌素，屠呦呦则因发现了抗疟疾药物青蒿素。天然产品对农业也非常重要，因为超过三分之一的农药是天然产品。细菌和真菌是生物活性物质的丰富来源，尤其具有吸引力，因为它们提供了可再生资源。虽然已经发现了许多天然产物，但近年来发现新的天然产物的速度有所下降。这可能对我们的日常生活产生深远的影响，例如，新抗生素的发现速度急剧下降，我们可能面临世界进入“后抗生素时代”的可能性。本提案的总体目标是开展天然产物化学和相关微生物学的基础研究，以开发创新的工具/方法来激发天然产物的发现。研究将沿着两条战线进行。一个重点将解决大板块计数异常，描述了在环境样本中只有1%的微生物可以培养的观察结果。这一过程的关键步骤是单个细菌培养物在分离细菌的环境中的“驯化期”。我们将开发和测试一种工具，我们相信它将大大提高微生物的培养比例。第二个重点将解决细菌和真菌中“沉默”的天然产物问题。这些被定义为在微生物DNA中编码的天然产物，但不是在标准条件下生产的。我们将研究一些单独和组合的方法来开发工具，以诱导生产沉默的天然产物。虽然在发现用于人类健康的天然产品方面作出了大量努力，但在兽医学方面的努力要少得多。这个项目将测试在这个研究项目中确定的新的天然产品，作为用于伴侣动物的抗菌剂。出于伦理原因，万古霉素等“最后手段”抗菌药物仅用于治疗人类感染，不得用于动物；因此，兽医学迫切需要发现新的抗生素来治疗耐药病原体引起的感染。总的来说，如果成功，拟议的研究将开发出大大提高新天然产物发现率的工具/方法。鉴于天然产物的各种应用，完成科学目标可能会产生重大影响。

Natural products have a well-documented track record of providing new active ingredients with a wide range of applications. Historically, one primary target area has been the pharmaceutical industry. As one example, the 2015 Novel Prize in Physiology or Medicine was jointly awarded to Campbell and Omura for the discovery of avermectins for the treatment of river blindness, and Tu for the discovery of the anti-malaria drug artemisinin. Natural products are also of great importance to the agriculture industry as over one third of all pesticides are natural products. Bacteria and fungi are prolific sources of bioactive agents and are particularly attractive as they provide a renewable resource. While numerous discoveries of natural products have been made, the rate of discovery of new natural products has declined in recent years. This could have a far-reaching effect on our daily lives as, for one example, the rate of discovery of new antibiotics has declined sharply and we may be facing the possibility of the world entering a "post-antibiotic era". The general aim of this proposal is to conduct basic research in natural products chemistry and associated microbiology to develop innovative tools/methods to invigorate natural product discovery. Research will proceed along two fronts. One focus will address the Great Plate Count Anomaly which describes the observation that only 1 % of microbes in an environmental sample can be cultured. The critical step in this process is a `domestication period' of individual bacterial cultures in the environment from which the bacteria were isolated. We will develop and test a tool that we believe will facilitate the culture of a greatly increased percentage of microbes. The second focus will address the issue of "silent" natural products in bacteria and fungi. These are defined as natural products that are encoded in a microbe's DNA but are not produced under standard conditions. We will investigate a number of approaches individually and in combination to develop tools to induce production of silent natural products. While there has been substantial effort in natural product discovery for applications in human health, there has been much less effort in veterinary medicine. This project will test new natural products identified in this research program for applications as antimicrobial agents for use in companion animals. For ethical reasons, `last resort' antimicrobials such as vancomycin are reserved solely for the treatment of infections in humans and are not to be used in animals; therefore, a pressing need exists in veterinary medicine for the discovery of novel antibiotics to treat infections caused by drug-resistant pathogens. Overall, if successful, the proposed research will develop tools/methods that will greatly enhance the rate of discovery of new natural products. Given the diverse applications of natural products, completion of the scientific goals could have a significant impact.