Marine microbial natural product discovery

鉴于天然产物对医学的重要性，它们对现代社会的影响是无可争辩的。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。虽然取得了显著的发现，但近年来天然产物的发现率有所下降，这深刻地影响了新疗法和相关制药和生物技术工业的发展。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，以开发创新方法来改进天然产物的发现。微生物（细菌和真菌）将是我们天然产品研究的来源，并将从海洋环境中获得。微生物非常有趣，因为它们通常可以很容易地发酵以产生所需数量的天然产物。海洋环境是一种尚未开发的微生物天然产物发现资源，从而提高了分离新化合物的可能性。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。该项目旨在确定新的海洋天然产品，用于家畜、伴侣动物和马的抗菌剂。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的MRSA感染，不能用于动物；因此，兽医学迫切需要发现新的抗生素来治疗新出现的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，从而使人们能够获得天然产物的新来源。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来有效地从大型复杂混合物中识别新的天然产物。最后，与兽药相关的抗菌检测将用于指导新的天然产物的分离和表征。总的来说，这项研究计划将开发研究方法，这将大大提高发现新的生物活性天然产物的速度。

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.