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着良好的记录。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联合授予坎贝尔和大村，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剂的丰富来源，并且由于它们提供可再生资源而特别有吸引力。虽然已经发现了许多天然产品，但近年来新天然产品的发现率有所下降。这可能对我们的日常生活产生深远影响，例如，新抗生素的发现率急剧下降，我们可能面临世界进入“后抗生素时代”的可能性。该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，以开发创新工具/方法，促进天然产物的发现。研究工作将沿着两条战线进行。一个焦点将解决大平板计数异常，其描述了环境样品中只有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，我们相信这将有助于培养大大增加百分比的微生物。第二个重点将解决细菌和真菌中“沉默”天然产物的问题。这些被定义为编码在微生物DNA中但不在标准条件下产生的天然产物。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品。虽然在人类健康应用的天然产品发现方面已经做出了大量努力，但在兽医学方面的努力要少得多。该项目将测试本研究计划中确定的新天然产品作为伴侣动物使用的抗菌剂的应用。出于伦理原因，万古霉素等“最后手段”抗菌剂仅用于治疗人类感染，而不用于动物;因此，兽医学迫切需要发现新的抗生素来治疗由耐药病原体引起的感染。总的来说，如果成功，拟议的研究将开发工具/方法，大大提高新的天然产品的发现率。鉴于天然产品的应用多种多样，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.