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.

Public Health Relevance

There is an unmet need for effective therapeutic agents for invasive fungal infections (candidiasis, aspergillosis, and mucormycosis) and protozoal parasite diseases (Chagas disease and leishmaniasis) along more effective therapeutic agents for cancers. The goals of this ICBG are to provide new therapeutic agents through a collaborative focus on high-value natural product leads produced by under-explored source of microbial diversity.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19TW009872-01
Application #
8785542
Study Section
Special Emphasis Panel (ZRG1-BCMB-H (50))
Program Officer
Katz, Flora N
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$557,024
Indirect Cost
$197,612
Name
Harvard Medical School
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Silva-Junior, Eduardo A; Ruzzini, Antonio C; Paludo, Camila R et al. (2018) Pyrazines from bacteria and ants: convergent chemistry within an ecological niche. Sci Rep 8:2595
Li, Hongjie; Sosa-Calvo, Jeffrey; Horn, Heidi A et al. (2018) Convergent evolution of complex structures for ant-bacterial defensive symbiosis in fungus-farming ants. Proc Natl Acad Sci U S A 115:10720-10725
Paludo, Camila R; Menezes, Cristiano; Silva-Junior, Eduardo A et al. (2018) Stingless Bee Larvae Require Fungal Steroid to Pupate. Sci Rep 8:1122
Van Arnam, Ethan B; Currie, Cameron R; Clardy, Jon (2018) Defense contracts: molecular protection in insect-microbe symbioses. Chem Soc Rev 47:1638-1651
Ortega, Humberto E; Batista Jr, João M; Melo, Weilan G P et al. (2017) Absolute Configurations of Griseorhodins A and C. Tetrahedron Lett 58:4721-4723
Ramadhar, Timothy R; Zheng, Shao-Liang; Chen, Yu-Sheng et al. (2017) The Crystalline Sponge Method: A Solvent-Based Strategy to Facilitate Noncovalent Ordered Trapping of Solid and Liquid Organic Compounds. CrystEngComm 19:4528-4534
Gemperline, Erin; Horn, Heidi A; DeLaney, Kellen et al. (2017) Imaging with Mass Spectrometry of Bacteria on the Exoskeleton of Fungus-Growing Ants. ACS Chem Biol 12:1980-1985
Wyche, Thomas P; Ruzzini, Antonio C; Schwab, Laura et al. (2017) Tryptorubin A: A Polycyclic Peptide from a Fungus-Derived Streptomycete. J Am Chem Soc 139:12899-12902
Adnani, Navid; Rajski, Scott R; Bugni, Tim S (2017) Symbiosis-inspired approaches to antibiotic discovery. Nat Prod Rep 34:784-814
Lewin, Gina R; Carlos, Camila; Chevrette, Marc G et al. (2016) Evolution and Ecology of Actinobacteria and Their Bioenergy Applications. Annu Rev Microbiol 70:235-54

Showing the most recent 10 out of 17 publications