Ribosomally encoded natural products were once thought to be of limited structural diversity and uncommon amongst microbes. Over the past few years, however, this viewpoint has changed due to the increased discovery rate of RNPs possessing newly described structural motifs previously ascribed to their nonribosomal counterparts. Nearly every sequenced genome, including invertebrates, contains the genetic capacity to biosynthesize ribosomally- encoded, post-translationally modified natural products such as lantibiotics, bacteriocins, microcins, cyanobactins, thiopeptides, and lasso peptides, thereby making this class of underappreciated natural products perhaps the most dominant in all of nature. What is lacking, however, is a systematic approach to harvest this ubiquitous class of natural products and assess their unique biosynthetic capacity. The difficulty associated with characterizing RNPs in a systematic fashion can be attributed to their falling outside the scope of not only most therapeutic screening programs but also metabolomic or proteomic approaches due to their larger size, structural diversity and extraordinary number of post-translational modifications. This proposal outlines the developmental strategies to create a set of tools for harnessing the biosynthetic potential of ribosomally encoded natural products through mass spectrometry based genome mining. The techniques and methodologies created as a result of the proposed work will not only be important for the detection of therapeutic lead compounds, but also for the efficient characterization of ribosomally encoded toxins secreted by pathogenic bacteria such as Staphylococcus aureus, Bacillus cereus and Clostridium difficile as well as defensins produced by higher eukaryotes such as marine snails, primates and humans.

Public Health Relevance

This work outlines an approach that experimentally mines genome sequences for genetically encoded molecules that control biology. Such molecules serve as great lead compounds for therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097509-03
Application #
8625312
Study Section
Enabling Bioanalytical and Imaging Technologies Study Section (EBIT)
Program Officer
Gerratana, Barbara
Project Start
2012-04-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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