This project addresses a key issue for both biology and medicine: the discovery of small molecules that can serve as the basis for regulating biological processes and/or developing therapeutic agents. Bacteria that live in close association with other organisms, symbiotic bacteria, produce small molecules to regulate the relations with their hosts and other community members, and researchers are just now beginning to appreciate the pervasiveness of these interactions and the legion of biologically active small molecules needed to maintain them. This proposal describes three different approaches to access these small molecules;two focus on specific symbioses, while the third focuses on a general strategy to intercept bacterial messages. 1) The first aim focuses on symbiotic bacteria that are expected to produce antibacterial, antifungal, and nematocidal compounds. Bacteria from several genera - Pseudomonas, Burkholderia, and Flavobacteria among others - are used by some social amoebas (Dictyostelium discoideum) to defend territory, deter predators, and provide a selective advantage over close relatives lacking bacterial symbionts.
This aim will find new sources for antimicrobial agents and reveal the genetic basis for virulence and antibiotic resistance in relatives of human pathogens. 2) The second aim focuses on symbiotic bacteria that provide a developmental signal for a model eukaryote. While the biomedical community has long appreciated the ability of certain bacteria to make the defensive small molecules that led to important antibiotic and anticancer agents, the recognition that bacteria also make small molecules that regulate animal development, metabolism and evolution is very recent. Hydroids with their complex multistage life history are an important model for animal development.
This aim will define the small molecule signal(s) that turns a free-swimming larva into a sessile hydroid. This project will provide important insights into the origins of the lipid signals that control much of human development. 3) The third specific aim focuses on a common strategy bacteria use to send small molecule messages to their neighbors: tiny vesicles that bud off from bacterial outer membranes called outer membrane vesicles (OMVs).
This aim will develop a generally applicable approach to systematically explore the metabolomics of these OMVs in order to quickly distinguish information carrying small molecules from the much less significant metabolic flotsam and jetsam found in bacterial communities.

Public Health Relevance

Improving human health depends on discovering molecules that improve on existing therapeutic agents or suggest new therapeutic agents. Many of our most effective drugs for infectious disease and cancer have come from environmental bacteria, which produce drug-like molecules to control their surroundings. This project will attempt to discover previously unknown molecules made by bacteria that live in close association with animals as potential therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM086258-05
Application #
8503293
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Gerratana, Barbara
Project Start
2008-09-09
Project End
2017-02-28
Budget Start
2013-04-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$409,545
Indirect Cost
$164,520
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Spady, Emma S; Wyche, Thomas P; Rollins, Nathanael J et al. (2018) Mammalian Cells Engineered To Produce New Steroids. Chembiochem 19:1827-1833
Böttcher, Thomas; Szamosvári, Dávid; Clardy, Jon (2018) A Repeating Sulfated Galactan Motif Resuscitates Dormant Micrococcus luteus Bacteria. Appl Environ Microbiol 84:
Beemelmanns, Christine; Ramadhar, Timothy R; Kim, Ki Hyun et al. (2017) Macrotermycins A-D, Glycosylated Macrolactams from a Termite-Associated Amycolatopsis sp. M39. Org Lett 19:1000-1003
Liu, Yizhou; Saurí, Josep; Mevers, Emily et al. (2017) Unequivocal determination of complex molecular structures using anisotropic NMR measurements. Science 356:
Guo, Huijuan; Rischer, Maja; Sperfeld, Martin et al. (2017) Natural products and morphogenic activity of ?-Proteobacteria associated with the marine hydroid polyp Hydractinia echinata. Bioorg Med Chem 25:6088-6097
Wyche, Thomas P; Ruzzini, Antonio C; Beemelmanns, Christine et al. (2017) Linear Peptides Are the Major Products of a Biosynthetic Pathway That Encodes for Cyclic Depsipeptides. Org Lett 19:1772-1775
Brancucci, Nicolas M B; Gerdt, Joseph P; Wang, ChengQi et al. (2017) Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum. Cell 171:1532-1544.e15
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
Rischer, Maja; Klassen, Jonathan L; Wolf, Thomas et al. (2016) Draft Genome Sequence of Shewanella sp. Strain P1-14-1, a Bacterial Inducer of Settlement and Morphogenesis in Larvae of the Marine Hydroid Hydractinia echinata. Genome Announc 4:
Böttcher, Thomas; Elliott, Hunter L; Clardy, Jon (2016) Dynamics of Snake-like Swarming Behavior of Vibrio alginolyticus. Biophys J 110:981-92

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