Chemoenzymatic synthesis of macrolactones utilizing PolyketideSynthases (PKSs) for the generation of novel macrolide antibiotics
利用聚酮化合物合成酶 (PKS) 化学酶法合成大环内酯,以生成新型大环内酯抗生素
基本信息
- 批准号:10674817
- 负责人:
- 金额:$ 1.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-02 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAmidesAnabolismAnti-Infective AgentsAntibiotic ResistanceAntibioticsAntineoplastic AgentsAreaBiochemicalBiological AssayCatalytic DomainCenters for Disease Control and Prevention (U.S.)Cessation of lifeChimeric ProteinsClinicalComplexCyclizationCytochrome P450Deoxy SugarsDevelopmentDirected Molecular EvolutionEconomicsEngineeringEnvironmentEnzymesErythromycinEstersEvaluationFamilyGatekeepingGenerationsGenetic TranscriptionHealthHumanHydroxylationImmunomodulatorsIn VitroIndustryInfectionMacrolidesMediatingMetabolic BiotransformationMethodsMixed Function OxygenasesMolecularMolecular MachinesNatural ProductsNaturePathway interactionsPharmaceutical PreparationsPharmacologic SubstancePositioning AttributeProcessProductionPropertyProteinsRare Earth MetalsReagentResearchResistanceRibosomesSeriesSynthesis ChemistrySystemTestingTherapeuticTylosinVariantWorkWorld Health Organizationanalogappendageaqueouscatalystcostdesignflexibilityglobal healthglycosylationglycosyltransferasehigh throughput screeningimprovedinterestmembermicroorganismmultidisciplinarymutantnovelnovel therapeuticsoxidationpathogenic bacteriapathogenic microbepicromycinpolyketide synthasepolyketidesscaffoldsecondary metabolitesmall moleculesynthetic enzymetherapeutically effectivetranslation assayvirtualwasting
项目摘要
Proposal Summary
The megasynthases that mediate construction of a vast array of natural products represent some of the most
complex molecular machines in Nature. In the Sherman group, polyketide synthases (PKSs) are of interest from
a multi-disciplinary perspective. PKSs are responsible for the biosynthesis of diverse secondary metabolites of
economic and therapeutic importance including antibiotics, anticancer agents and immune-modulators. Antibiotic
resistance is one of the biggest threats of global health according to the World Health Organization (WHO). The
Centers for Disease Control and Prevention (CDC) showed that in the US alone, it causes more than 2 million
infections and 23,000 deaths a year. These alarming numbers are estimated to continue incrementally every
year, with 10 million estimated deaths worldwide in 2050. For these reasons, we are motivated to utilize PKSs
to facilitate the design and generation of novel antibiotics from the macrolides class to improve the development
of new, effective therapeutics.
A diverse subset of PKSs generate macrocyclic ring systems that are essential for macrolide production, include
pathways from the Pikromycin (Pik), Erythromycin (DEBS) and Tylosin (Tyl) producing microorganisms. In this
project, I will be focusing on the use of synthetic approaches to facilitate assembly of these compounds and
their analogs using biocatalysis and enzyme engineering. The synthesis of diverse polyketide chain elongation
intermediates in conjunction with late-stage biosynthetic machinery (e.g. glycosyltransferases, P450
monooxygenases) facilitates efficient access to a repertoire of novel molecules, which are challenging to
generate using synthetic methods alone. PKS enzymes provide a powerful method to selectively catalyze key
transformations on polyketide chains to generate macrolactones, which can be subsequently converted to novel
macrolide antibiotics.
Previous work in the Sherman lab has revealed that the primary hurdle to applying PKS modules for the
production of diverse macrolactones hinges on the selectivity of the Pik thioesterase (TE) domain. These findings
suggested that the TE functions as a gatekeeper in the processing of unnatural substrates to generate novel
macrocycles. In the proposed research, I plan to (1) Design and synthesize unnatural substrates to explore PKS
selectivity and tolerance toward substrate loading, elongation, and cyclization for the generation of odd-
membered ring macrolactones, (2) Pursue a TE directed evolution approach for improved total turnover, and
expansion of substrate scope to generate new macrolactone products, (3) Apply chemoenzymatic synthesis for
diverse macrolides and determine their bioactivity profile against human bacterial pathogens. These efforts will
be crucial to developing new macrolide antibiotics to control and overcome emerging resistance in human
bacterial pathogens and to improve therapeutic parameters in this important class of anti-infective agents.
建议总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Maria Luisa Adrover-Castellano其他文献
Maria Luisa Adrover-Castellano的其他文献
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{{ truncateString('Maria Luisa Adrover-Castellano', 18)}}的其他基金
Chemoenzymatic synthesis of macrolactones utilizing PolyketideSynthases (PKSs) for the generation of novel macrolide antibiotics
利用聚酮化合物合成酶 (PKS) 化学酶法合成大环内酯,以生成新型大环内酯抗生素
- 批准号:
10311658 - 财政年份:2021
- 资助金额:
$ 1.78万 - 项目类别:
Chemoenzymatic synthesis of macrolactones utilizing PolyketideSynthases (PKSs) for the generation of novel macrolide antibiotics
利用聚酮化合物合成酶 (PKS) 化学酶法合成大环内酯,以生成新型大环内酯抗生素
- 批准号:
10470751 - 财政年份:2021
- 资助金额:
$ 1.78万 - 项目类别:
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