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

• 批准号: 8785542
• 负责人: Jon Clardy
• 金额: $ 90.7万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 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/8785542
• 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; Genomics; 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

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）：一个国际生物多样性合作小组（ICBG），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，将发现和开发巴西共生细菌生产的治疗剂。该团队将针对三个治疗领域：1）传染性真菌病原体，2）查加斯病和利什曼病，以及3）血液癌症-所有这三个都是对人类健康的主要威胁，需要用新的治疗药物来解决。在国际上，侵袭性真菌疾病造成的死亡人数超过疟疾或结核病，而恰加斯病给巴西带来了特殊的负担，造成的死亡人数与结核病一样多。在巴西人口中，利什曼病现在已经超过了恰加斯病。尽管癌症化疗取得了重大进展，但预计今年全球癌症将导致800万人死亡（占所有死亡人数的13%，WHO），预计到2030年每年将导致1300万人死亡。该ICBG集中了所有三种疾病的筛选平台，将执行从初级筛选到体内小鼠模型研究的所有必要步骤。ICBG将专注于从巴西社会昆虫的细菌共生体中识别有用的天然产品，如真菌生长的蚂蚁。真菌生长的蚂蚁有专门的细菌共生体，可以提供化学防御来对抗威胁它们社区的病原真菌。细菌产生的化学防御的生态作用-杀死病原真菌，但保留真菌花园和昆虫宿主-匹配的抗真菌，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种变体的机会，从而促进鉴定具有更好药物潜力的活性化合物（例如，较低的哺乳动物毒性，改善的药代动力学）。我们的发现工作将广泛使用尖端技术和基因组方法。将对细菌进行微培养以进行高通量初步表型筛选，并对优先菌株进行再培养以进行二次筛选和去复制。将对所有细菌菌株进行基因分型（16 S），并对沿沿着管道前进的菌株进行基因组测序并进行生物信息学分析。从我们密集的采样，表型测定，化学表征和基因组测序产生的数据将提供重要的见解巴西微生物多样性和生态环境和进化选择的天然产品，他们生产。此外，ICBG将大力培训巴西科学家，并支持该国药物发现的发展。