De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity
De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity
批准号:
10242923
负责人:
JAMES E KIRBY
金额:
$77.26万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-08-20 至 2024-07-31
关键词:
Acinetobacter baumanniiAcylationAddressAminesAmino SugarsAminoglycoside AntibioticsAminoglycoside resistanceAminoglycosidesAnti-Bacterial AgentsAnti-Infective AgentsAntibiotic ResistanceAntibioticsBypassCarbohydrate ChemistryCarbohydratesCenters for Disease Control and Prevention (U.S.)ChargeChemicalsCoupledCryoelectron MicroscopyDiaminesESKAPE pathogensEnzymesEventFrequenciesGoalsHydrogen BondingHydroxyl RadicalIncidenceInfectionLaboratoriesLeadMediatingMetabolismMethodologyMethylationMethyltransferaseMicrobiologyModificationMulti-Drug ResistanceOrganismOutcomeParentsPharmaceutical ChemistryPositioning AttributePseudomonas aeruginosaPyrimidinePyrimidinesResistanceRibosomesRouteSchemeSiteSite-Directed MutagenesisStructureStructure-Activity RelationshipTherapeuticVariantanalogantimicrobialbacterial resistancebactericidebasecarbapenem-resistant Enterobacteriaceaecarbohydrate structureclinically relevantdesignemerging antimicrobial resistanceexpectationimprovedmulti-drug resistant pathogennephrotoxicitynovelototoxicitypathogenpathogenic bacteriapolyolpreservationprotonationpyridineresistance mechanismstereochemistrystructural biologysugartargeted treatmenttv watching
中文摘要
有一个新的威胁来自多重耐药革兰氏阴性细菌病原体,具体来说,
碳青霉烯类耐药肠杆菌科,鲍曼不动杆菌,和铜绿假单胞菌(例如,
ESKAPE病原体)。由此产生的感染通常无法治疗或只能用有毒药物治疗。
抗菌剂更令人不安的是,这些感染的发生率正在增加,
频率.因此,疾病预防控制中心现在将这些微生物归类为最大的抗生素耐药性威胁
水平迫切需要新的抗感染策略。该多PI R 01申请提出了一种重新分类
药物化学设计和从头碳水化合物合成方法,当与
功能表征和冷冻EM使结构导向设计应该导致快速发现
具有抗耐药革兰氏阴性病原体活性的新型氨基糖苷类(AG)抗菌剂。
长期预期成果是:1)建立新的综合方法学,
药物化学基于SAR的氨基糖苷类化学空间的探索和2)发现
具有改进的抗耐药细菌活性的新的氨基糖苷类结构基序(例如,AME、RMT-
介导的抗性)。指导我们方法的基本假设是,
许多碳水化合物结构由于传统的合成限制而未被发现,
碳水化合物和半合成方法。相比之下,我们的完全从头合成方法使得
以立体化学选择性的方式安装更广泛的碳水化合物。的实例
将探索的结构变异是具有稀有氨基糖、直链糖和2-
脱氧链霉胺(2-DOS)取代,旨在避免已知的氨基糖苷类耐药性
机制等
英文摘要
There is an emerging threat from multidrug-resistant Gram-negative bacterial pathogens, specifically,
carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa (e.g.,
ESKAPE pathogens). The resulting infections are often untreatable or treatable only with toxic
antimicrobials. More troubling is the fact that the incidences of these infections are occurring with increasing
frequency. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat
level. New anti-infective strategies are urgently needed. This multi-PI R01 application proposes a de novo
medicinal chemistry design and de novo carbohydrate synthesis approach, which when coupled with
functional characterization and cryo-EM enabled structure-guided design should lead to the rapid discovery
of novel aminoglycoside (AG) antimicrobials with activity against resistant Gram-negative pathogens.
The long-term expected outcomes are 1) the establishment of new synthetic methodology for systematic
medicinal chemistry SAR-based exploration of the aminoglycoside chemical space and 2) the discovery of
new aminoglycoside structural motifs with improved activity against resistant bacteria (e.g., AME, RMT-
mediated resistance). The underlying hypothesis that guides our approach is the assumption that there are
many carbohydrate structures that remain undiscovered due to the synthetic limitations of traditional
carbohydrate and semi-synthetic approaches. In contrast, our total de novo synthetic approach enables the
installation of a much broader range of carbohydrates in a stereochemically selective manner. Examples of
structural variations that will be explored are aminoglycosides with rare aminosugar, linear sugar, and 2-
deoxystreptamine (2-DOS) substitutions that are designed to evade known aminoglycoside resistance
mechanisms.
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会议论文
De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity
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批准号:10676201
-
项目类别:
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资助金额:$75.72万
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财政年份:2020
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负责人:JAMES E KIRBY
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依托单位:
Use of De Novo Synthesis Approaches and Structure-guided Design to Optimize Therapeutic Properties of Streptothricin Class Antimicrobials
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批准号:10469007
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项目类别:
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资助金额:$77.22万
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财政年份:2020
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负责人:JAMES E KIRBY
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依托单位:
De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity
-
批准号:10447128
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项目类别:
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资助金额:$76.53万
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财政年份:2020
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负责人:JAMES E KIRBY
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依托单位:
Use of De Novo Synthesis Approaches and Structure-guided Design to Optimize Therapeutic Properties of Streptothricin Class Antimicrobials
-
批准号:10269053
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项目类别:
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资助金额:$77.75万
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负责人:JAMES E KIRBY
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依托单位:
Use of De Novo Synthesis Approaches and Structure-guided Design to Optimize Therapeutic Properties of Streptothricin Class Antimicrobials
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Plasmid Eviction to Restore Susceptibility in Carbapenem-Resistant Enterobacteriaceae
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财政年份:2015
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负责人:JAMES E KIRBY
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依托单位:
VALIDATION OF A HIGH THROUGHPUT SCREEN FOR KPC PLASMID EVICTION
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批准号:8990439
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Novel Antimicrobials Targeting Bacterial Type IV Secretion Systems
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批准号:8439168
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资助金额:$39.0万
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财政年份:2012
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负责人:JAMES E KIRBY
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依托单位:
Novel Antimicrobials Targeting Bacterial Type IV Secretion Systems
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批准号:9123514
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项目类别:
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资助金额:$39.15万
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财政年份:2012
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负责人:JAMES E KIRBY
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依托单位:
Novel Antimicrobials Targeting Bacterial Type IV Secretion Systems
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批准号:8549945
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资助金额:$36.8万
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财政年份:2012
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负责人:JAMES E KIRBY
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依托单位:
Type IV Secretion System Therapeutics
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批准号:7896197
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项目类别:
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资助金额:$21.71万
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财政年份:2010
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依托单位:
Type IV Secretion System Therapeutics
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批准号:8041056
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资助金额:$25.84万
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财政年份:2010
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依托单位:
Non-Antibiotic Selectable Markers for Bacillus Anthracis
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批准号:7565913
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资助金额:$34.83万
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负责人:JAMES E KIRBY
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依托单位:
Non-Antibiotic Selectable Markers for Bacillus Anthracis
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批准号:7472107
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项目类别:
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资助金额:$21.25万
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财政年份:2008
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负责人:JAMES E KIRBY
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The Basis of Anthrax-Induced Vascular Damage
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资助金额:$21.25万
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依托单位:
The Basis of Anthrax-Induced Vascular Damage
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批准号:7140530
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资助金额:$20.75万
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财政年份:2005
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LEGIONELLA PNEUMOPHILA VIRULENCE FACTORS DEFINED IN VIVO
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海外基金