The Discovery of New Antibiotics from Deep Sea Actinomycete Bacteria

描述（由申请人提供）：本申请旨在建立一个海洋抗生素药物发现的合作项目，该项目由斯克里普斯海洋研究所的William Fenical与医学与药学院的维克托Nizet联合领导，他们都是圣地亚哥加州大学的研究人员。该计划利用了最近的发现，即新的，遗传多样性和化学丰富的放线菌细菌，抗生素的经典资源，居住在深海沉积物。该计划强调创新的免疫和毒力因子为基础的方法在抗感染药物筛选再加上尝试和真正的全细胞生物测定方法的抑菌和杀菌活性。该研究计划的总体目标是将Fenical实验室的海洋微生物学和天然产物化学专业知识与Nizet实验室的分子微生物学和传染病专业知识相结合，以建立一种独特的长期合作，以发现有效对抗耐药细菌和真菌病原体的新抗生素。为了实现这一目标，将制定逐步发现和开发计划，重点是发现具有前所未有的结构和显著体内活性的新分子。该计划将重点筛选海洋放线菌培养物提取物组分（每年超过3，500种），以对抗当前关注的耐药人类病原体，包括耐甲氧西林金黄色葡萄球菌（MRSA），耐万古霉素粪肠球菌（VREF），铜绿假单胞菌，多重耐药鲍曼不动杆菌和耐氟康唑白色念珠菌。此外，创新的，非细胞杀伤试验将涉及，其中包括抑制两个关键的毒性因子的主要细菌病原体，金色类胡萝卜素色素的S。金黄色葡萄球菌的成孔溶细胞毒素链球菌溶血素S（GAS），以及通过诱导巨噬细胞和嗜中性粒细胞中的全局转录调节因子HIF-1来增强宿主先天免疫功能的测定。新的抗生素将被分离，结构确定和体外筛选，以对抗超过35种其他人类病原体的扩大小组。当定义了足够有效的抗生素时，它们将被推进到小鼠体内测定系统中，用于MRSA（对于经典抗生素）、HIF-1（先天免疫增强剂或色素抑制剂）或GAS（对于SLS抑制剂）的全身和局部感染模型中的治疗功效，Nizet实验室对此具有丰富的经验。多达10种最有前途的新抗生素也将进行有限数量的更先进的临床前评价，包括急性小鼠毒性、抗菌作用动力学、耐药性发展能力和抗生素后效应。符合候选药物严格要求的化合物将被推进到合作行业或通过衍生项目在UCSD内部开发。公共卫生相关性。耐药传染病的持续出现已经造成了国家卫生保健紧急情况，每年约有200万人在美国医院获得细菌感染，90，000人因此死亡;这些感染中约70%对至少一种药物具有耐药性。本申请建立了具有（A）海洋科学和天然产物化学家和（B）细菌发病机理和传染病方面专业知识的实验室之间的合作计划。该团队将发现并表征来自深海海洋微生物的新型抗生素，这些抗生素可有效对抗多种耐药细菌和真菌病原体，从而为医疗保健从业者提供传染病治疗的关键新方法。

DESCRIPTION (provided by applicant): This application seeks to establish a collaborative program in marine antibiotic drug discovery headed by William Fenical from the Scripps Institution of Oceanography in association with Victor Nizet from the Schools of Medicine & Pharmacy, both faculty researchers at the University of California, San Diego. The program capitalizes on the recent discovery that new, genetically-diverse and chemically-rich actinomycete bacteria, the classic resource for antibiotics, reside in deep-ocean sediments. The program emphasizes innovative immunological and virulence factor-based approaches in anti-infective drug screening coupled with tried and true whole cell bioassay methods for bacteriostatic and bactericidal activities. The overall goal of this research program is to merge the marine microbiology and natural products chemistry expertise of the Fenical lab with the molecular microbiology and infectious disease expertise of the Nizet lab to establish a unique and long-term collaboration to discover new antibiotics effective against drug-resistant bacterial and fungal pathogens. To achieve this goal, a step-wise discovery and development program will be set in place that emphasizes the discovery of new molecules with unprecedented structures and significant in vivo activity. The program will focus on screening marine actinomycete culture extract fractions (more than 3,500 per year) against drug-resistant human pathogens of immediate concern, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VREF), Pseudomonas aeruginosa, multi drug-resistant Acinetobacter baumannii, and fluconazole-resistant Candida albicans. In addition, innovative, non-cell-kill assays will be involved, which include inhibition of two critical virulence factors of the leading bacterial pathogens, the golden carotenoid pigment of S. aureus, the pore-forming cytolytic toxin streptolysin S of group A Streptococcus (GAS), as well as an assay to boost the host innate immune function via induction of the global transcriptional regulator HIF-1 in macrophages and neutrophils. New antibiotics will be isolated, structurally defined and screened in vitro against an expanded panel of more than 35 other human pathogens. When sufficiently potent antibiotics are defined, they will be advanced to murine in vivo assay systems for therapeutic efficacy in systemic and localized infection models for MRSA (for classical antibiotic), HIF-1 (innate immune enhancement or pigment inhibition agents) or GAS (for SLS inhibition agents) with which the Nizet laboratory has extensive experience. Up to ten of the most promising new antibiotics will also undergo a limited number of more advanced preclinical evaluations including acute mouse toxicity, kinetics of antimicrobial effect, capacity for resistance development, and post-antibiotic effect. Compounds that meet the stringent requirements to be considered drug candidates will be advanced to collaborating industries or developed within UCSD through spin-off projects. PUBLIC HEALTH RELEVANCE. The continued emergence of drug-resistant infectious diseases has created a National health care emergency to which the approximately 2 million people acquire bacterial infections in U.S. hospitals each year, and 90,000 die as a result; approximately 70% of those infections are resistant to at least one drug. This application establishes a collaborative program between laboratories with expertise in (A) marine science and natural product chemists and (B) bacterial pathogenesis and infectious disease. The team will discover and characterize novel antibiotics from deep ocean marine microbes that are effective against several drug-resistant bacterial and fungal pathogens, thus providing heath care practitioners with critical new approaches to infectious disease therapy.