Novel therapeutic agents from the bacterial symbionts of Brazilian invertebrates

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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.