Synthesis and Evaluation of Narrow-Spectrum Antibiotics Targeting MRSA
针对MRSA的窄谱抗生素的合成与评价
基本信息
- 批准号:9981542
- 负责人:
- 金额:$ 14.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlkynesAmericanAminoglycosidesAnabolismAnti-Bacterial AgentsAntibiotic ResistanceAntibioticsBacterial Antibiotic ResistanceBacterial InfectionsBiochemicalBiochemistryBiologicalBiological AssayCell WallCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeChemicalsChemistryClinicalColistinComplexCoupledCrystallizationDataDevelopmentEscherichia coliEvaluationGenesGenomic approachGoalsHumanLabelLibrariesLightMacrolidesMedicineMetabolicMethodologyMethodsMinimum Inhibitory Concentration measurementModificationMolecular BiologyNatural ProductsOrganismPatientsPeptidoglycanPharmacologic SubstancePharmacopoeiasPropertyProteomicsReportingResistanceResistance developmentResortRiskRoentgen RaysSeptic ShockStaphylococcus aureusStructureStructure-Activity RelationshipSuperbugTestingTetracyclinesVancomycinVancomycin-resistant S. aureusactivity-based protein profilingadductanalogbacterial resistancebasebeta-Lactamscomputational chemistrycytotoxicitydesignfallsgenome sequencingglobal healthimprovedinhibitor/antagonistlead candidatemethicillin resistant Staphylococcus aureusmolecular modelingmutantnovelnovel therapeuticspathogenic bacteriaresistance frequencyresponsescaffoldseptic patientstoolwhole genome
项目摘要
Project Summary/Abstract
Natural products account for two-thirds of the antibacterial pharmacopeia and are therefore privileged
scaffolds. These complex molecules have inspired novel synthetic methods and positively impacted the fields
of biochemistry, molecular biology, and medicine. The proposed project is inspired by albocycline, a
unique 14-membered macrolactone with potent, narrow-spectrum activity against the “superbug” methicillin-
resistant Staphylococcus aureus (MRSA). We have validated that albocycline is effective against MRSA and
vancomycin-resistant S. aureus strains; moreover, it is non-toxic to human cells.
In 2013, Tomoda reported that albocycline inhibited peptidoglycan (i.e., bacterial cell wall) synthesis in
macromolecular assays. Using biochemical assays and molecular modeling, we demonstrated that albocycline
was a weak (mM) inhibitor of MurA from S. aureus. Consistent with its narrow-spectrum profile, albocycline did
not inhibit MurA from E. coli. Based on our results and those of Tomoda, we conclude it must have additional
bacterial targets. Significantly, we recently completed a modular, step-efficient total synthesis of the natural
product driven by novel chemistry of N-sulfinyl metallodienamines. Accordingly, in Aim 1 we propose to
prepare albocycline analogs (including probes) by semi- and diverted total synthesis to explore the chemical
space about this privileged scaffold. In Aim 2, we will co-crystallize albocycline in complex with MurA based on
exciting preliminary results and employ structure-based analog design. We will also identify the target(s) of
albocycline to determine its mode-of-action using computational chemistry, chemical proteomics and genomics
approaches, in addition to a novel metabolic labeling methodology. Finally, in Aim 3 we will evaluate the
biological activity of all albocycline analogs.
At the end of the four-year project period, we will have (1) a deeper understanding of how albocycline
exerts its antibacterial action; (2) a library of tool compounds and antibiotic lead candidates that selectively
modulate their target(s); and most significantly, (3) a bona fide launching point for the development of novel,
narrow-spectrum antibiotics to treat recalcitrant MRSA, VISA, and VRSA (i.e., the project's long-term goal).
项目总结/文摘
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Synthesis and biological evaluation of semi-synthetic albocycline analogs.
- DOI:10.1016/j.bmcl.2020.127509
- 发表时间:2020-11-01
- 期刊:
- 影响因子:2.7
- 作者:Daher SS;Franklin KP;Scherzi T;Dunman PM;Andrade RB
- 通讯作者:Andrade RB
Alternative approaches utilizing click chemistry to develop next-generation analogs of solithromycin.
- DOI:10.1016/j.ejmech.2022.114213
- 发表时间:2022-04-05
- 期刊:
- 影响因子:6.7
- 作者:Daher, Samer S.;Lee, Miseon;Jin, Xiao;Teijaro, Christiana N. N.;Barnett, Pamela R. R.;Freundlich, Joel S. S.;Andrade, Rodrigo B. B.
- 通讯作者:Andrade, Rodrigo B. B.
Staphylococcus aureus resistance to albocycline can be achieved by mutations that alter cellular NAD/PH pools.
- DOI:10.1016/j.bmc.2021.115995
- 发表时间:2021-02-15
- 期刊:
- 影响因子:3.5
- 作者:Scherzi T;D'Ambrosio EA;Daher SS;Grimes CL;Dunman PM;Andrade RB
- 通讯作者:Andrade RB
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RODRIGO B ANDRADE其他文献
RODRIGO B ANDRADE的其他文献
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{{ truncateString('RODRIGO B ANDRADE', 18)}}的其他基金
Enantioselective Total Synthesis of (+)-Halichlorine
( )-卤氯的对映选择性全合成
- 批准号:
6847444 - 财政年份:2004
- 资助金额:
$ 14.5万 - 项目类别:
Enantioselective Total Synthesis of (+)-Halichlorine
( )-卤氯的对映选择性全合成
- 批准号:
6742018 - 财政年份:2004
- 资助金额:
$ 14.5万 - 项目类别:
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