The need for new antibiotics continues to grow more dire. Natural products from microbial sources have supplied the major pipeline for novel antibiotics, but traditional discovery efforts have yielded diminishing returns over the last severl decades, necessitating new approaches. This proposal uses the powerful approach of aligning chemical ecology with natural product discovery, exploiting the highly productive chemistry of bacteria associated with fungus-farming ants. These highly specialized ant-associated bacteria are thought to defend their niche using antibiotics against closely related competitors. The chemical basis of this antagonism has not been explored and is the foundation of this project.
The first aim of this project is to screen ant-associated bacteria to identify antibacterial activiy and other chemically mediated interactions. Second, the molecules responsible for this activity will be identified and characterized. Genome sequencing will connect these active molecules to their biosynthetic gene clusters and also reveal which additional clusters are present but silent - that is, no corresponding metabolites are observed. These cryptic biosynthetic clusters are a near-universal feature of bacterial genomes and are a major opportunity for antibiotic discovery.
The third aim uses ecologically inspired co-culturing approaches to supply missing chemical cues that elicit production of some of these cryptic metabolites. These chemical inducers of antibiotic production will be identified, tested for general utility, and applied to elicit additioal cryptic metabolites.

Public Health Relevance

Novel antibiotics are desperately needed, and aligning chemical ecology with antibiotic discovery is a promising approach to efficiently deliver new lead therapeutics. This proposal leverages the highly productive chemistry of ant-associated symbiotic bacteria to discover new antibiotics and also chemical tools to recover additional 'hidden' antibiotics from bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM117661-02
Application #
9243921
Study Section
Special Emphasis Panel (ZRG1-F04A-W (20)L)
Program Officer
Barski, Oleg
Project Start
2016-06-01
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$59,166
Indirect Cost
Name
Harvard Medical School
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Van Arnam, Ethan B; Ruzzini, Antonio C; Sit, Clarissa S et al. (2016) Selvamicin, an atypical antifungal polyene from two alternative genomic contexts. Proc Natl Acad Sci U S A 113:12940-12945