Small molecule natural products, primarily of microbial origin, have been extensively used as therapeutic agents for decades. Most searches to identify and characterize such compounds have been dominated either by efforts that seek activities that inhibit microbial growth (antibiotics) or simply by the chemical identification of microbial products without any defined knowledge of their biological function. In recent years, we have begun to recognize that many microbial products serve as signals sensed by diverse microbes as part of the way they adapt to their environment. Based on this ecological perspective of the role of natural products we have developed our central hypothesis: Bacteria synthesize and secrete a large number of small signaling molecules that affect the physiology of other microbes that occupy the same habitat. While this is the general hypothesis driving the proposed research, the lines of experimentation we propose are also discovery-driven:
we aim to discover new small molecules that mediate diverse interspecies interactions in the microbial world. The expectation is that by identifying and characterizing such molecules, and studying their biosynthetic pathways and biological functions, we will generate a collection of potential lead compounds. These could eventually be developed as therapeutic agents, either as antibiotics to treat bacterial infections or, as several other natural products currently in clinical use demonstrate, to alleviate other afflictions. To address the question of signaling compounds synthesized by bacteria in a way that will lead to the discovery of many such molecules we have devised approaches that meld the disciplines of microbial ecology, physiology, and genetics, with enzymology, bioinformatics, and small molecule chemistry. In this multidisciplinary manner we will undertake three specific aims: (1) Prospecting for novel microbial signaling molecules, (2) Genome mining by metabolite stimulation, and (3) Characterization of new small molecules: biosynthesis and biological activity. Relevance to public health: The development of antibiotics as therapeutics is one of the key accomplishments of modern medicine. Unfortunately, the appearance of antibiotic resistant bacteria has diminished the effectiveness of existing antiobiotics. The proposed research aims at discovering new antibiotics and other agents with therapeutic potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082137-04
Application #
7837756
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2010-06-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$556,174
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Gontang, Erin A; Aylward, Frank O; Carlos, Camila et al. (2017) Major changes in microbial diversity and community composition across gut sections of a juvenile Panchlora cockroach. PLoS One 12:e0177189
Segev, Einat; Wyche, Thomas P; Kim, Ki Hyun et al. (2016) Dynamic metabolic exchange governs a marine algal-bacterial interaction. Elife 5:
Segev, Einat; Castañeda, Isla S; Sikes, Elisabeth L et al. (2016) Bacterial influence on alkenones in live microalgae. J Phycol 52:125-30
Segev, Einat; Tellez, Adèle; Vlamakis, Hera et al. (2015) Morphological Heterogeneity and Attachment of Phaeobacter inhibens. PLoS One 10:e0141300
Cleto, S; Van der Auwera, G; Almeida, C et al. (2014) Genome Sequence of Serratia plymuthica V4. Genome Announc 2:
Lambert, Stéphany; Traxler, Matthew F; Craig, Matthias et al. (2014) Altered desferrioxamine-mediated iron utilization is a common trait of bald mutants of Streptomyces coelicolor. Metallomics 6:1390-9
Seyedsayamdost, Mohammad R; Wang, Rurun; Kolter, Roberto et al. (2014) Hybrid biosynthesis of roseobacticides from algal and bacterial precursor molecules. J Am Chem Soc 136:15150-3
Romero, Diego; Sanabria-Valentin, Edgardo; Vlamakis, Hera et al. (2013) Biofilm inhibitors that target amyloid proteins. Chem Biol 20:102-10
Chen, Yun; Yan, Fang; Chai, Yunrong et al. (2013) Biocontrol of tomato wilt disease by Bacillus subtilis isolates from natural environments depends on conserved genes mediating biofilm formation. Environ Microbiol 15:848-864
Leiman, Sara A; May, Janine M; Lebar, Matthew D et al. (2013) D-amino acids indirectly inhibit biofilm formation in Bacillus subtilis by interfering with protein synthesis. J Bacteriol 195:5391-5

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