SBIR Phase I: Novel Antibiotics from Marine Animal-Microbe Symbioses

这个小型企业创新研究(SBIR)第一阶段项目将开发一种新的平台技术，利用以前无法获得的微生物多样性来发现新的广谱抗生素。该项目的重点是海洋无脊椎动物和微生物之间的共生，这些微生物已知是具有潜在治疗价值的新型生物活性化合物的丰富来源。长期以来，微生物共生体一直被怀疑是此类化合物的实际生产者。它们和其他微生物在很大程度上仍未被开发，因为超过99%的微生物不能在实验室中培养。海水中可培养微生物的回收率特别差(0.1-0.01%)，使？海洋物种特别吸引人。该公司采用了一种全新的方法来原位培养以前未培养的微生物，显著提高了环境细菌的可培性，从传统技术的1%提高到20%。在第一阶段，该公司将采用和优化这种方法，专门从海洋共生体中获取微生物，从海洋海绵和珊瑚中分离出新的微生物物种，并探索它们的抗菌性能。这项建议的主要智力价值和创新之处在于，重点关注抗菌剂的一种基本新来源，即与海洋无脊椎动物相关的微生物，并使用一种新的方法来培养这些微生物。该项目更广泛的影响/商业潜力源于对具有新作用模式的新抗生素的日益增长的需求，这些新抗生素不容易受到当前耐药机制的影响。美国传染病学会和世界卫生组织的抗菌素可获得性工作组等机构已经公布了耐药性问题的紧迫性和即将开发的抗生素的缺乏。多重抗药性细菌正是该公司瞄准的病原体。尽管大型制药公司基本上已经放弃了他们的抗生素发现计划，但他们仍然对获得新的可行的抗生素感兴趣。全球抗生素市场价值超过250亿美元。收入最高的公司，如Levaquin、Zosyn和Augentin，2008年的销售额超过10亿美元，这三家公司都已经出现了明显的阻力。即使是窄谱抗生素，也有一个迫切的、尚未得到满足的需求和市场。它们的商业价值和社会重要性怎么强调都不为过。尤其重要的是，拟议的研究不仅将导致选择新的抗菌剂，而且将产生一个新的技术平台，形成一个全新的新疗法流水线。

This Small Business Innovation Research (SBIR) Phase I project will develop a new platform technology to exploit previously inaccessible microbial diversity to discover novel broad-spectrum antibiotics. The project focuses on symbioses between marine invertebrates and microorganisms known to be rich sources of novel bioactive compounds with potential therapeutic value. Microbial symbionts have long been suspected to be the actual producers of such compounds. They, and other microorganisms in general, remain largely unexplored because over 99% of them cannot be cultivated in the laboratory. Recovery of cultivable microorganisms from the sea is especially poor (0.1 to 0.01%) making the ?missing? marine species particularly attractive. The company employs a radically new method for in situ cultivation of previously uncultured microorganisms that significantly raises the cultivability of environmental bacteria, from 1% using traditional technologies to 20%. In Phase I, the company will adopt and optimize this method to access microorganisms specifically from marine symbioses, isolate novel microbial species from marine sponges and corals, and explore their antimicrobial properties. The principle intellectual merit and innovation of this proposal is in focusing on an essentially novel source of antimicrobials, microbes living in association with marine invertebrates, and the use of a novel method to grow these microbes.The broader impact/commercial potential of this project stems from an increasing need for new antibiotics with new modes of action that are not susceptible to current resistance mechanisms. Agencies such as the Antimicrobial Availability Task Force of the Infectious Diseases Society of America and the World Health Organization have publicized the urgency of the resistance problem and the lack of forthcoming antibiotics in development. The multiple antibiotic-resistant bacteria are the exact pathogens that the company is targeting. Although big Pharma has largely abandoned their antibiotic discovery programs, they remain interested in acquiring new viable antibiotics. The global market for antibiotics is over $25 billion. Top earners, such as Levaquin (Floxin), Zosyn, and Augmentin have 2008 sales over $1 billion, with significant resistance already observed to all three. There is also an acute, unmet need and market even for narrow-spectrum antibiotics. Their commercial value and societal importance cannot be overstated. Of particular importance is that the proposed research will not only lead to a selection of novel antimicrobials, but to a new technology platform forming a whole new pipeline of new therapeutics.