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 #
5R01GM086258-06
Application #
8638023
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
2014-03-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$415,317
Indirect Cost
$170,292
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Beemelmanns, Christine; Woznica, Arielle; Alegado, Rosanna A et al. (2014) Synthesis of the rosette-inducing factor RIF-1 and analogs. J Am Chem Soc 136:10210-3
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Bottcher, Thomas; Kolodkin-Gal, Ilana; Kolter, Roberto et al. (2013) Synthesis and activity of biomimetic biofilm disruptors. J Am Chem Soc 135:2927-30
Kolodkin-Gal, Ilana; Cao, Shugeng; Chai, Liraz et al. (2012) A self-produced trigger for biofilm disassembly that targets exopolysaccharide. Cell 149:684-92

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