Marine microbial natural product discovery

天然产物对现代社会的影响是无可争议的，因为它们对医学的重要性。例如，在过去25年中，42%的抗癌药物和47%的抗感染药物是天然产品。虽然取得了令人瞩目的发现，但近年来天然产品的发现率有所下降，深刻影响了新疗法和相关制药和生物技术行业的发展。该提案的总体目标是在天然产物化学和相关微生物学方面进行基础研究，以开发创新方法来改善天然产物的发现。微生物（细菌和真菌）将是我们天然产品调查的来源，并将从海洋环境中获得。微生物是非常感兴趣的，因为它们通常可以容易地发酵以产生所需量的天然产物。海洋环境是发现微生物天然产物的一个未充分开发的资源，从而提高了分离新化合物的可能性。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。该项目旨在确定新的海洋天然产品，作为抗菌剂应用于牲畜、伴侣动物和马。出于伦理原因，“最后手段”的抗微生物剂如万古霉素仅保留用于治疗人类MRSA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紧急耐药病原体引起的感染。总的来说，该提案寻求开发分离海洋微生物的新方法，从而能够获得新的天然产品来源。此外，它旨在开发新的方法来诱导微生物发酵中的天然产物生产，并寻求开发一种新的化学工具，以有效地从大量复杂的混合物中识别新的天然产物。最后，与兽医学相关的抗微生物测定将用于指导新天然产物的分离和表征。总的来说，该研究计划将开发研究方法，大大提高新的生物活性天然产物的发现率。

SummaryThe impact of natural products on modern society is indisputable given their importance to medicine. As one example, 42% of anticancer and 47% of anti-infective agents introduced over the past 25 years are natural products. While remarkable discoveries have been made, the rate of natural product discovery has declined in recent years, profoundly affecting the development of new therapeutics and the related pharmaceutical and biotechnology industries. The general aim of this proposal is to conduct basic research in natural products chemistry and associated microbiology to develop innovative methods to improve natural product discovery. Microbes (bacteria and fungi) will be the source of our natural products investigations and will be obtained from marine environments. Microbes are of great interest as they can generally be readily fermented to produce required amounts of natural product. The marine environment represents an underexplored resource for microbial natural product discovery thus improving the likelihood of isolating new compounds. 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 aims to identify new marine natural products with applications as antimicrobial agents for use in livestock animals, companion animals and horses. For ethical reasons, ‘last resort’ antimicrobials such as vancomycin are reserved solely for the treatment of MRSA 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 emergent drug-resistant pathogens. Overall, the proposal seeks to develop new methods for the isolation of marine-derived microbes thus allowing access to new sources of natural products. Further, it aims to develop new methods to induce natural product production in microbial fermentation and seeks to develop a new chemical tool to efficiently identify new natural products from large sets of complex mixtures. Lastly, antimicrobial assays of relevance to veterinary medicine will be used to guide the isolation and characterization of new natural products. Overall, this research program will develop research methods that will greatly enhance the rate of discovery of new bioactive natural products.