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合作项目，由斯克里普斯海洋学研究所的 William Fenical 和医学与药学院的 Victor Nizet 领导，两人都是加州大学圣地亚哥分校的教员研究人员。该计划利用了最近的发现，即深海沉积物中存在着遗传多样性丰​​富且化学成分丰富的新放线菌，这是抗生素的经典资源。该计划强调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经过验证的全细胞生物测定方法。该研究项目的总体目标是将 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，建立独特的长期合作关系，以发现有效对抗耐药细菌和真菌病原体的新型抗生素。为了实现这一目标，将制定逐步的发现和开发计划，强调发现具有前所未有的结构和显着体内活性的新分子。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、多重耐药菌 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试验，其中包括对主要细菌病原体的两种关键毒力因子的抑制，即金黄色葡萄球菌的金色类胡萝卜素色素、A组链球菌（GAS）的成孔溶细胞毒素链球菌溶血素S，以及通过诱导全局转录调节因子来增强宿主先天免疫功能的试验。 巨噬细胞和中性粒细胞中的 HIF-1。新抗生素将在体外针对超过 35 种其他人类病原体进行分离、结构确定和筛选。当确定足够有效的抗生素后，它们将被推进到小鼠体内检测系统中，以在 MRSA（经典抗生素）、HIF-1（先天免疫增强剂或色素抑制剂）或 GAS（SLS 抑制剂）的全身和局部感染模型中获得治疗效果，Nizet 实验室在这方面拥有丰富的经验。多达十种最有前途的新型抗生素也将接受有限数量的更先进的临床前评估，包括小鼠急性毒性、抗菌作用动力学、耐药性发展能力和抗生素后效应。满足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加州大学圣地亚哥分校内部开发。公共卫生相关性。耐药传染病的不断出现，造成了全国医疗卫生紧急状态，美国每年约有200万人在医院里受到细菌感染，9万人因此死亡；大约 70% 的感染对至少一种药物具有耐药性。该应用程序在具有 (A) 海洋科学和天然产物化学家以及 (B) 细菌发病机制和传染病专业知识的实验室之间建立了合作计划。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，从而为卫生保健从业者提供治疗传染病的重要新方法。