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.
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.
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