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 #
5R01GM097509-02
Application #
8448101
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
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$452,607
Indirect Cost
$143,808
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Mohimani, Hosein; Gurevich, Alexey; Mikheenko, Alla et al. (2017) Dereplication of peptidic natural products through database search of mass spectra. Nat Chem Biol 13:30-37
Crüsemann, Max; O'Neill, Ellis C; Larson, Charles B et al. (2017) Prioritizing Natural Product Diversity in a Collection of 146 Bacterial Strains Based on Growth and Extraction Protocols. J Nat Prod 80:588-597
Maansson, Maria; Vynne, Nikolaj G; Klitgaard, Andreas et al. (2016) An Integrated Metabolomic and Genomic Mining Workflow To Uncover the Biosynthetic Potential of Bacteria. mSystems 1:
Nguyen, Don D; Melnik, Alexey V; Koyama, Nobuhiro et al. (2016) Indexing the Pseudomonas specialized metabolome enabled the discovery of poaeamide B and the bananamides. Nat Microbiol 2:16197
Cha, Jae-Yul; Han, Sangjo; Hong, Hee-Jeon et al. (2016) Microbial and biochemical basis of a Fusarium wilt-suppressive soil. ISME J 10:119-29
Spraker, Joseph E; Sanchez, Laura M; Lowe, Tiffany M et al. (2016) Ralstonia solanacearum lipopeptide induces chlamydospore development in fungi and facilitates bacterial entry into fungal tissues. ISME J 10:2317-30
Zhang, Weipeng; Lu, Liang; Lai, Qiliang et al. (2016) Family-wide Structural Characterization and Genomic Comparisons Decode the Diversity-oriented Biosynthesis of Thalassospiramides by Marine Proteobacteria. J Biol Chem 291:27228-27238
Wang, Mingxun; Carver, Jeremy J; Phelan, Vanessa V et al. (2016) Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat Biotechnol 34:828-837
Liaw, Chih-Chuang; Chen, Pei-Chin; Shih, Chao-Jen et al. (2015) Vitroprocines, new antibiotics against Acinetobacter baumannii, discovered from marine Vibrio sp. QWI-06 using mass-spectrometry-based metabolomics approach. Sci Rep 5:12856
Luzzatto-Knaan, Tal; Melnik, Alexey V; Dorrestein, Pieter C (2015) Mass spectrometry tools and workflows for revealing microbial chemistry. Analyst 140:4949-66

Showing the most recent 10 out of 34 publications