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，由斯克里普斯海洋学研究所的William Fenical领导，与来自加州大学圣地亚哥分校医学院的Victor Nizet合作。该项目利用了最近的一项发现，即深海沉积物中存在着新的、基因多样的、化学成分丰富的放线菌细菌，这是抗生素的经典资源。该计划强调在抗感染药物筛选中采用创新的免疫学和毒力因子为基础的方法，并结合经过验证和真正的全细胞生物测定方法来测定抑菌和杀菌活性。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结合起来，建立一种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抗生素。为了实现这一目标，将建立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。该项目将重点筛选海洋放线菌培养提取物组分（每年超过3500个），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，将涉及创新的非细胞杀伤试验，其中包括抑制主要细菌病原体的两种关键毒力因子，金黄色葡萄球菌的金色类胡萝卜素色素，A群链球菌（GAS）的成孔细胞溶解毒素streptolysin 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来增强宿主先天免疫功能的试验。新的抗生素将被分离、结构确定并在体外针对超过35种其他人类病原体进行筛选。当足够有效的抗生素被确定时，它们将被推进到小鼠体内检测系统，用于MRSA（经典抗生素），HIF-1（先天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，Nizet实验室在这方面有丰富的经验。多达10种最有希望的新抗生素还将进行有限数量的更先进的临床前评估，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。符合严格要求的化合物被认为是候选药物，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开发。公共卫生相关性。耐药传染病的持续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，9万人因此死亡；这些感染中大约70%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一个协作计划。该团队将从深海海洋微生物中发现并鉴定新型抗生素，这些抗生素对几种耐药细菌和真菌病原体有效，从而为卫生保健从业者提供传染病治疗的关键新方法。