The emergence of antibiotic resistance has created a global dilemma for the need to discover newantibacterialleadagents.Realizingthiscriticalneedfornewantibacterialagentswithnew structuretypesandtargets,wefocushereonthebiosyntheticinterrogationanddevelopmentof structurally distinct marine bacterial natural products. An underlying theme associated with manymarinemicrobialantibioticsinvolvestheuseofaromaticpolyketideframeworksthathave undergone extensive oxidative tailoring reactions catalyzed by halogenase and oxygenase biosynthetic enzymes. In this application, we propose a multidisciplinary project involving heterologous biosynthesis, mechanistic enzymology, atomic resolution protein X-ray crystallography,chemoenzymaticsynthesis,andgeneticengineeringtounderstandandcontrol themolecularbasisofpolyketidediversificationinaseriesofmarinebacterialcompoundswith promising antimicrobial properties. To accomplish the broad goals outlined in this application, weproposefourspecificaims.First,weplantofunctionallyandstructurallycharacterizediverse meroterpenoid V-dependent chloroperoxidases and their catalytic properties in promoting antimicrobial chemical diversity. Second, we will discover, characterize, and engineer biosynthetic pathways for structural diversification of halogenated pyrrole containing bioactive natural products. Third, we aim to functionally characterize the unprecedented biosynthesis of thiotetronic acid polyketide antibiotics and apply new biosynthetic reactions to extend the synthesis and bioengineering of novel molecules. And fourth, we will interrogate the antimicrobial activity and mechanism of new meroterpenoid, bipyrrole, and thiotetronate compounds.

Public Health Relevance

The majority of clinically used antibiotics are derived from nature, and of those, most are produced by related soil bacteria. Realizing the critical need for new antibiotics to combat increasing bacterial resistance to known antibiotic drugs, antibacterial agents from marine microbes are emerging as promising drug leads due to their distinctive chemical structures. This application investigates novel biosynthetic enzymes that construct and diversify polyketide antibiotics from underexplored marine bacteria. Anticipated outcomes of this research project will be the discovery of new biosynthetic reactions in natural product diversification and the application of this basic knowledge to the (chemoenzymatic) synthesis and bioengineering of designer agents for biological evaluation in antibacterial screens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Xu, Zuoyu
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University of California, San Diego
Earth Sciences/Resources
La Jolla
United States
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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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