Novel therapeutic agents from the bacterial symbionts of Brazilian invertebrates

来自巴西无脊椎动物细菌共生体的新型治疗剂

基本信息

批准号：
8902965
负责人：
Jon Clardy
金额：
$ 85.25万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8902965
关键词：
Address Amoeba genus Animal Testing Animals Antifungal Agents Antineoplastic Agents Antiprotozoal Agents Ants Area Aspergillosis Bacteria Behavioral Behavioral Genetics Biodiversity Bioinformatics Biological Assay Biological Factors Brazil Candidiasis Cataloging Catalogs Cells Cessation of life Chagas Disease Chemicals Chemotherapy-Oncologic Procedure Clinical Communities Country Coupled Data Development Discipline Disease Drug Kinetics Effectiveness Family Farming environment Focus Groups Fractionation Genomic approach Genotype Goals Growth Health Hematopoietic Neoplasms Human Human Cell Line Individual Insecta International Invertebrates Knowledge Laboratories Leadership Leishmaniasis Malaria Malignant Neoplasms Metabolic Microbe Mucormycosis Mycoses Natural Products Chemistry Parasites Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phylogenetic Analysis Physicians Plants Play Population Principal Component Analysis Protozoa Public Health Recording of previous events Research Resistance Ribosomal RNA Role Sampling Scientist Source Staging Symbiosis System Technology Therapeutic Therapeutic Agents Toxic effect Training Transcription Factor AP-1 Transcription Factor AP-2 Alpha Variant Work arm base drug discovery field study fungus genome sequencing high throughput screening improved in vivo insight killings member metabolomics microbial mouse model novel novel therapeutics pathogen programs screening small molecule small molecule libraries social success therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): An International Cooperative Biodiversity Group (ICBG) with an interdisciplinary leadership team of physicians, pharmacologists, evolutionary biologists, and chemists will discover and develop therapeutic agents produced by Brazilian symbiotic bacteria. The team will target three therapeutic areas: 1) infectious fungal pathogens, 2) Chagas disease and leishmaniasis, and 3), cancers of the blood-all three of which represent major threats to human health that need to be addressed with new therapeutic agents. Internationally, invasive fungal diseases kill more people than malaria or TB, while Chagas disease imposes a special burden on Brazil, killing as many Brazilians as TB. Leishmaniasis has now passed Chagas disease in the Brazilian population. In spite of major improvements in cancer chemotherapy, cancer is projected to result in 8 million deaths internationally this year (13% of all deaths, WHO) and an estimated 13 million per year by 2030. This ICBG has focused screening platforms for all three diseases that will perform all the required steps from primary screens through in vivo mouse model studies. The ICBG will focus on identifying useful natural products from bacterial symbionts of social insects in Brazil, such as fungus-growing ants. Fungus-growing ants have specialized bacterial symbionts that provide chemical defenses against pathogenic fungi that threaten their communities. The ecological role of the bacterially produced chemical defenses - killing pathogenic fungi but sparing the fungal gardens and the insect host - matches the therapeutic requirements for antifungal, anticancer, and antiprotozoal agents. The population level diversity of the bacterial producers also provides the opportunity to identify multiple variants of a structural family, facilitating identification of active compounds ith better drug potential (e.g., lower mammalian toxicity, improved pharmacokinetics). Our discovery efforts will make extensive use of cutting-edge technology and genomic approaches. Bacteria will be micro-cultured for high-throughput primary phenotypic screens, and priority strains will be re-cultured for secondary screens and dereplication. All bacterial strains will be genotyped (16S), and strains advancing along pipelines will have their genomes sequenced and subjected to bioinformatic analysis. The data generated from our intensive sampling, phenotypic assays, chemical characterization, and genome sequencing will provide important insights into Brazilian microbial diversity and the ecological context and evolutionary selection of the natural products they produce. In addition, the ICBG will undertake major efforts to train Brazilian scientists, and support the development of drug discovery in the country.

描述（由申请人提供）：国际生物多样性合作组织（ICBG）拥有由医生、药理学家、进化生物学家和化学家组成的跨学科领导团队，将发现和开发由巴西共生细菌产生的治疗剂。该团队将针对三个治疗领域：1）传染性真菌病原体，2）恰加斯病和利什曼病，3）血液癌症——这三种疾病对人类健康构成了重大威胁，需要用新的治疗药物来解决。在国际上，侵袭性真菌病导致的死亡人数比疟疾或结核病还要多，而查加斯病给巴西带来了特殊负担，导致巴西死亡人数与结核病一样多。在巴西人口中，利什曼病现已通过恰加斯病传播。尽管癌症化疗取得了重大进展，但预计今年全球将有 800 万人因癌症死亡（世界卫生组织统计，占所有死亡人数的 13%），到 2030 年预计每年将有 1300 万人死亡。该 ICBG 重点关注所有三种疾病的筛查平台它将执行从初级筛选到体内小鼠模型研究的所有必需步骤。 ICBG 将重点从巴西社会性昆虫（例如真菌蚂蚁）的细菌共生体中识别有用的天然产物。生长真菌的蚂蚁拥有专门的细菌共生体，可以针对威胁其群落的病原真菌提供化学防御。细菌产生的化学防御的生态作用——杀死病原真菌，但不伤害真菌花园和昆虫宿主——符合抗真菌、抗癌和抗原虫剂的治疗要求。细菌生产者的群体水平多样性还提供了鉴定结构家族的多个变体的机会，有助于鉴定具有更好药物潜力（例如，较低的哺乳动物毒性、改善的药代动力学）的活性化合物。我们的发现工作将广泛利用尖端技术和基因组方法。细菌将被微培养以进行高通量初级表型筛选，优先菌株将被重新培养以进行二级筛选和去复制。所有细菌菌株都将进行基因分型 (16S)，并且沿着管道推进的菌株将对其基因组进行测序并进行生物信息学分析。我们的密集采样、表型分析、化学表征和基因组测序产生的数据将为了解巴西微生物多样性及其产生的天然产物的生态背景和进化选择提供重要见解。此外，ICBG 将大力培训巴西科学家，并支持该国药物研发的发展。