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

这项小企业创新研究（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。该项目侧重于海洋无脊椎动物和微生物之间的共生关系，这些微生物是具有潜在治疗价值的新型生物活性化合物的丰富来源。微生物共生体长期以来一直被怀疑是这些化合物的实际生产者。它们和一般的其他微生物在很大程度上仍未被探索，因为99%以上的微生物无法在实验室培养。海洋中可培养微生物的回收率特别差（0.1 ~ 0.01%），这使得？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养性，从传统技术的1%提高到20%。在第一阶段，该公司将采用并优化该方法从海洋共生体中特异性获取微生物，从海洋海绵和珊瑚中分离新的微生物物种，并探索其抗菌性能。这一建议的主要知识价值和创新之处在于关注一种本质上新的抗菌剂来源，与海洋无脊椎动物生活在一起的微生物，以及使用一种新的方法来培养这些微生物。该项目的更广泛影响/商业潜力源于对具有不受当前耐药机制影响的新作用方式的新抗生素的日益增长的需求。美国传染病学会的抗微生物药物供应工作队和世界卫生组织等机构已经宣传了耐药性问题的紧迫性以及正在开发的抗生素的缺乏。这种具有多种抗生素耐药性的细菌正是该公司瞄准的病原体。尽管大型制药公司已经在很大程度上放弃了它们的抗生素发现项目，但它们仍然对获得新的可行抗生素感兴趣。全球抗生素市场超过250亿美元。收入最高的药物，如左旋喹（氟氧嘧啶）、佐辛（Zosyn）和奥格门汀（Augmentin）， 2008年的销售额超过10亿美元，但这三种药物已经出现了明显的耐药性。即使是窄谱抗生素，也存在着迫切的、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。特别重要的是，拟议的研究不仅会导致新的抗菌剂的选择，而且会形成一个新的技术平台，形成一个全新的新疗法管道。

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.