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: 7608702
• 负责人: William Fenical
• 金额: $ 45.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-07 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608702
• 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由Scripps海洋学研究所领导的海洋抗生素药物发现的合作计划，与加州大学圣地亚哥分校的教职员工研究人员合作，由医学与药学学院的Victor Nizet合作。该计划利用了最近的发现，即新的，遗传多样性和化学富裕的放线菌细菌（抗生素的经典资源）居住在深海沉积物中。该计划强调了抗感染药物筛查中基于创新的免疫和毒力因子的方法，并结合了肽抑制性和杀菌活性的尝试和真实的全细胞生物测定方法。该研究计划的总体目的是将Fenical Lab的海洋微生物学和天然产品化学专业知识与Nizet Lab的分子微生物学和感染性疾病专业知识合并，以建立独特的长期合作，以发现有效的针对药物抗药性细菌和真菌病原体的新抗生素。为了实现这一目标，将制定一个逐步的发现和开发计划，该计划强调发现具有前所未有结构和重要体内活性的新分子。该计划将着重于筛查海洋放线菌培养提取物分数（每年超过3500个），以针对抗药性的直接关注的耐药性病原体，包括耐甲氧西林金黄色葡萄球菌（MRSA），万古霉素 - vanosycin-耐药的faecalis faecalis（vref），peseosisters， + pseosistans， baumannii acinetobacter和抗氟康唑的白色念珠菌。此外，还将涉及创新的非细胞杀菌测定法，其中包括抑制主要细菌病原体的两个关键毒力因子，金黄色葡萄球菌的黄金类胡萝卜素色素，孔形成细胞溶解的细胞溶解毒素链霉素S组的A组A组链球菌（气体）的整体均可构想，并允许宿主的全体式启用宿主的启用宿主的启用，以构成现代宿主的功能。巨噬细胞和中性粒细胞中的HIF-1。新的抗生素将被隔离，结构定义和在体外进行筛查，并针对其他35多个人类病原体的扩展面板。当定义了足够有效的抗生素时，它们将在MRSA（用于经典抗生素），HIF-1（先天性免疫或色素抑制剂）或GAS（用于SLS抑制剂量抑制剂量的实验性经验）中，将它们推向体内和体内测定系统的治疗功效，以实现MRSA（用于经典的抗生素）（用于经典抗生素）（用于经典抗生素）（用于经典抗生素）的治疗疗效。多达十种最有希望的新抗生素还将进行有限的更先进的临床前评估，包括急性小鼠毒性，抗菌作用的动力学，耐药性发展的能力和抗抗生素后作用。满足要视为候选药物的严格要求的化合物将推进合作行业或通过衍生项目在UCSD内开发的化合物。公共卫生相关性。耐药性感染疾病的持续出现造成了国家医疗保健紧急情况，每年约有200万人在美国医院收到细菌感染，结果90,000人死亡；这些感染中约有70％对至少一种药物具有抵抗力。该应用建立了具有（a）海洋科学和天然产品化学家的专业知识的实验室之间的协作计划，以及（b）细菌发病机理和传染病。该小组将发现并表征深海海洋微生物的新型抗生素，这些抗生素有效地抵抗了几种耐药细菌和真菌病原体，从而为健康护理从业人员提供了关键的感染性疾病治疗方法。