Novel therapeutic agents from the bacterial symbionts of Brazilian invertebrates

描述（由申请人提供）：一个由医生、药理学家、进化生物学家和化学家组成的跨学科领导团队组成的国际合作生物多样性小组（ICBG）将发现和开发由巴西共生细菌产生的治疗药物。该团队将针对三个治疗领域：1)感染性真菌病原体，2)恰加斯病和利什曼病，以及3)血癌——这三个领域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，侵袭性真菌疾病导致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，导致巴西人死亡的人数与结核病一样多。利什曼病现已在巴西人口中超过恰加斯病。尽管在癌症化疗方面取得了重大进展，但预计今年国际上将有800万人死于癌症（占世卫组织所有死亡人数的13%），到2030年估计每年将有1300万人死于癌症。该ICBG侧重于所有三种疾病的筛查平台，这些平台将执行从初级筛查到体内小鼠模型研究的所有必要步骤。ICBG将专注于从巴西的群居昆虫（如真菌生长的蚂蚁）的细菌共生体中识别有用的天然产物。真菌生长的蚂蚁有专门的细菌共生体，这些共生体提供化学防御，抵御威胁其群落的病原真菌。细菌产生的化学防御的生态作用——杀死致病真菌，但保留真菌花园和昆虫宿主——与抗真菌、抗癌和抗原虫药物的治疗要求相匹配。细菌生产者的种群水平多样性也提供了鉴定结构家族的多个变体的机会，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。细菌将被微培养用于高通量的初级表型筛选，优先菌株将被重新培养用于二次筛选和去复制。所有菌株都将被基因分型（16S），沿着管道前进的菌株将被测序并进行生物信息学分析。从我们的密集采样、表型分析、化学表征和基因组测序中产生的数据将为巴西微生物多样性、生态环境和它们产生的天然产物的进化选择提供重要的见解。此外，ICBG将作出重大努力，培训巴西科学家，并支持该国的药物发现发展。

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.