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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Macromolecular Structure and Function E Study Section (MSFE)
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Xu, Zuoyu
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University of California San Diego
Schools of Earth Sciences/Natur
La Jolla
United States
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Teufel, Robin; Kaysser, Leonard; Villaume, Matthew T et al. (2014) One-pot enzymatic synthesis of merochlorin A and B. Angew Chem Int Ed Engl 53:11019-22
Diethelm, Stefan; Teufel, Robin; Kaysser, Leonard et al. (2014) A multitasking vanadium-dependent chloroperoxidase as an inspiration for the chemical synthesis of the merochlorins. Angew Chem Int Ed Engl 53:11023-6
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