Marine microbes have recently emerged as an important resource of chemically distinct antimicrobial agents with the potential to contribute significantly to the treatment of infectious diseases. An underlying theme associated with many marine microbial antibiotics involves the use of aromatic polyketide frameworks that have undergone extensive oxidative tailoring reactions catalyzed by halogenase and oxygenase biosynthetic enzymes. The marine microbial polyketide antibiotics enterocin, napyradiomycin, merochlorin, and marinopyrrole each boast unique structural features that result from dedicated oxidative tailoring reactions that contribute to their potent biological activities. In this appliction, we propose a multidisciplinary project involving heterologous biosynthesis, in vivo and in vitro biochemical analysis, and atomic resolution protein x-ray crystallography to understand the molecular basis of polyketide diversification in this series of marine microbial natural products. To accomplish the broad goals outlined in this application, we propose four specific aims. First, we plan to functionally and structurally characterize the enterocin EncM flavoprotein and explore its anticipated favorskiiase catalytic activity. Second, we will functionally and structurally characterize the napyradiomycin V-dependent chloroperoxidases and their catalytic properties in halogen-assisted meroterpenoid cyclization. Third, we aim to genetically and biochemically interrogate the biosynthesis of merochlorin C and its macrocyclizing V-dependent chloroperoxidase. And fourth, we will functionally characterize the biosynthesis of the marinopyrrole antibiotics and their novel bipyrrole coupling enzymology.

Public Health Relevance

Marine sediments have recently been shown to harbor unique microbial communities that produce chemically distinct antimicrobial agents with the potential to contribute significantly to the treatment of infectious diseases. This application investigates set of biosynthetic enzymes that introduce structure complexity and conformational constraints into novel polyketide antibiotics from marine bacteria. The ability to understand and rationally manipulate biosynthetic enzymes provides opportunities to expand natural product chemical diversity for the discovery and development of new drug candidates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047818-15
Application #
8810207
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Xu, Zuoyu
Project Start
2000-08-01
Project End
2016-02-29
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
15
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Zoology
Type
Earth Sciences/Resources
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Murray, Lauren A M; McKinnie, Shaun M K; Pepper, Henry P et al. (2018) Total Synthesis Establishes the Biosynthetic Pathway to the Naphterpin and Marinone Natural Products. Angew Chem Int Ed Engl 57:11009-11014
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Tang, Xiaoyu; Li, Jie; Moore, Bradley S (2017) Minimization of the Thiolactomycin Biosynthetic Pathway Reveals that the Cytochrome P450 Enzyme TlmF Is Required for Five-Membered Thiolactone Ring Formation. Chembiochem 18:1072-1076
Teufel, Robin; Agarwal, Vinayak; Moore, Bradley S (2016) Unusual flavoenzyme catalysis in marine bacteria. Curr Opin Chem Biol 31:31-9
El Gamal, Abrahim; Agarwal, Vinayak; Diethelm, Stefan et al. (2016) Biosynthesis of coral settlement cue tetrabromopyrrole in marine bacteria by a uniquely adapted brominase-thioesterase enzyme pair. Proc Natl Acad Sci U S A 113:3797-802
Ray, Lauren; Yamanaka, Kazuya; Moore, Bradley S (2016) A Peptidyl-Transesterifying Type?I Thioesterase in Salinamide Biosynthesis. Angew Chem Int Ed Engl 55:364-7

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