The Discovery of New Antibiotics from Deep Sea Actinomycete Bacteria

从深海放线菌中发现新抗生素

• 批准号: 7931427
• 负责人: William Fenical
• 金额: $ 45.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931427
• 关键词: Acinetobacter baumannii; Actinobacteria class; Actinomyces; Acute; Anti-Infective Agents; Antibiotics; Antimicrobial Effect; Bacteria; Bacterial Infections; Biological Assay; Biological Factors; California; Candida albicans; Caring; Carotenoids; Cells; Characteristics; Chemicals; Clinical; Clinical Trials; Collaborations; Communicable Diseases; Contracts; Coupled; Crude Extracts; Culture Media; Data; Databases; Development; Drug Formulations; Drug resistance; Emergency Situation; Enterococcus faecalis; Environment; Evaluation; Experimental Models; Faculty; Fluconazole resistance; Focal Infection; Goals; Grant; Head; Healthcare; Hospitals; Housing; Human; Immune; Immune system; In Vitro; Industry; Infection; Institution; Joints; Kinetics; Laboratories; Lead; Libraries; Licensing; Marines; Methods; Microbe; Microbiology; Modeling; Molecular; Multi-Drug Resistance; Mus; Natural Products Chemistry; Oceanography; Oceans; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacy facility; Phase; Phylogenetic Analysis; Pigments; Preclinical Drug Evaluation; Preclinical Testing; Process; Production; Program Development; Pseudomonas aeruginosa; Research; Research Personnel; Resistance; Resistance development; Resources; Sampling; Science; Screening procedure; Sea; Septicemia; Sequence Analysis; Series; Solid; Staphylococcus aureus; Streptococcus; Streptococcus pyogenes; Streptolysins; Structure; System; Techniques; Testing; Toxic effect; Toxin; Treatment Efficacy; Universities; Vancomycin resistant enterococcus; Virulence; Virulence Factors; X-Ray Crystallography; bactericide; base; cell killing; design; drug candidate; drug discovery; drug resistant bacteria; experience; fungus; immune function; in vitro Assay; in vivo; innovation; liquid chromatography mass spectrometry; macrophage; medical schools; meetings; methicillin resistant Staphylococcus aureus; microbial; model design; mouse model; neutrophil; novel; novel strategies; pathogen; preclinical evaluation; programs; public health relevance; rRNA Genes; response; staphyloxanthin; two-dimensional

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.

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，由斯克里普斯海洋研究所的William Fenical领导，与医学院和药学院的Victor Nizet合作，他们都是加州大学圣地亚哥分校的教职研究人员。该项目利用了最近的一项发现，即新的、遗传多样性和化学成分丰富的放线菌细菌--抗生素的经典来源--存在于深海沉积物中。该计划强调在抗感染药物筛选中基于免疫学和毒力因子的创新方法，以及用于抑菌和杀菌活性的成熟和真实的全细胞生物测定方法。这项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品化学专业知识与Nizet实验室的分子微生物学和传染病专业知识相结合，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，将制定一个循序渐进的发现和开发计划，强调发现具有前所未有的结构和显著的体内活性的新分子。该计划将重点筛选海洋放线菌培养提取物部分(每年超过3500个)，以对抗人类直接关注的耐药病原体，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，还将涉及创新的非细胞杀伤性分析，包括抑制主要细菌病原体的两个关键毒力因素，金黄色葡萄球菌的金黄色胡萝卜素色素，A组链球菌(GAS)的穿孔溶细胞素S，以及通过诱导巨噬细胞和中性粒细胞中的全球转录调节因子HIF-1来增强宿主的先天免疫功能。新的抗生素将被分离、结构定义和体外筛选，以对抗超过35种其他人类病原体的扩大小组。当足够有效的抗生素被定义后，它们将被推进到小鼠体内测试系统，用于Nizet实验室拥有丰富经验的MRSA(经典抗生素)、HIF-1(天然免疫增强或色素抑制剂)或GAS(SLS抑制剂)的全身和局部感染模型的治疗效果。多达10种最有希望的新抗生素也将接受有限数量的更高级的临床前评估，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。符合被认为是候选药物的严格要求的化合物将被推进到合作行业或通过剥离项目在加州大学圣迭戈分校开发。与公共卫生相关。耐药传染病的不断出现造成了全国卫生保健紧急情况，每年约有200万人在美国医院感染细菌，导致9万人死亡；其中约70%的感染至少对一种药物产生抗药性。该应用程序建立了在(A)海洋科学和天然产品化学家以及(B)细菌致病和传染病方面具有专业知识的实验室之间的合作计划。该团队将从深海海洋微生物中发现并表征新型抗生素，这些抗生素对几种抗药性细菌和真菌病原体有效，从而为卫生保健从业者提供关键的传染病治疗新方法。