Actions of spiropyrimidinetriones against bacterial type II topoisomerases
螺嘧啶三酮对细菌 II 型拓扑异构酶的作用
基本信息
- 批准号:10750473
- 负责人:
- 金额:$ 3.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAddressAffectAmino AcidsAnti-Bacterial AgentsBacillus anthracisBacterial Drug ResistanceBacterial InfectionsBindingBiochemicalBiological AssayBiological ModelsCell Death ProcessCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeCiprofloxacinClinicalComparative StudyComplexDNADNA Double Strand BreakDNA Topoisomerase IVDataDevelopmentDrug toxicityDrug-resistant Neisseria GonorrhoeaeEnzyme InteractionEnzymesEscherichia coliFluorescence AnisotropyFluoroquinolonesGeneticGenetic MaterialsGenetic RecombinationGenetic TranscriptionGenetic studyGenomeGeometryGoalsGonorrheaGrowthHumanImpairmentIn VitroInfectionInfertilityMeasuresMediatingMethodsMonitorMultienzyme ComplexesMutationNeisseria gonorrhoeaeNeurofibrillary TanglesPelvic Inflammatory DiseasePersonsPharmaceutical PreparationsPositioning AttributeReactionRecommendationResistanceResistance developmentSOS ResponseSite-Directed MutagenesisStressSuperhelical DNASystemTopoisomeraseTopoisomerase IITopoisomerase InhibitorsToxinWorkantimicrobial resistant infectioncellular targetingclinically relevantcytotoxicdesigndrug developmentds-DNAfluoroquinolone resistanceimprovedin vivomutantnovelnovel therapeuticspathogenpharmacophorephase III trialresistance mutationresponsetargeted agenttooltreatment guidelines
项目摘要
PROJECT SUMMARY
Antibacterial resistant infections cause more than 1.2 million deaths around the world each year, and this
number is predicted to grow to 10 million by 2050 unless resistance is effectively curbed. A pathogen of particular
concern is drug-resistant Neisseria gonorrhoeae, which is listed as one of five “urgent threats” (the highest threat
level) by the Centers for Disease Control and Prevention (CDC). Fluoroquinolones (FQs) were recommended
as frontline treatment for the 98 million annual cases of gonorrhea since 1993, but their use was discontinued in
2007 due to increasing levels of target-mediated resistance. This resistance occurs when specific mutations in
the target for FQs, the bacterial type II topoisomerases, gyrase and topoisomerase IV, arise in response to FQ
treatment. One strategy to overcome resistance is to develop new compounds that interact with bacterial type II
topoisomerases at amino acid residues distinct from those of FQs. Using this approach, a new class of
gyrase/topoisomerase IV-targeted agents with a spiropyrimidinetrione (SPT) pharmacophore was identified.
Gyrase and topoisomerase IV regulate the topological state of DNA in bacterial cells. These essential
enzymes control levels of DNA supercoiling (over- and underwinding) and remove knots and tangles from the
genetic material by passing an intact double helix through a transient double-stranded DNA break generated in
a separate DNA segment. Both FQs and SPTs stabilize the covalent enzyme-cleaved DNA complex (cleavage
complex) such that when advancing replication and transcription machinery approach these complexes, they
can fragment the genome, triggering the SOS response and other cell death processes. The primary goal of this
project is to overcome FQ resistance in N. gonorrhoeae by increasing our understanding of SPT interactions
with gyrase and topoisomerase IV and target-mediated resistance development across bacterial species to
inform the design of more potent and efficacious antibacterials. This goal will be addressed by three specific aims:
In Specific Aim 1, I will assess the actions of SPTs against gyrase and topoisomerase IV from N.
gonorrhoeae, Bacillus anthracis, and Escherichia coli to determine how the activities of this class varies across
bacterial species. To this end, I will use assays that measure DNA cleavage, cleavage complex stability, and
catalytic inhibition with wild-type enzymes. In Specific Aim 2, I will evaluate the ability of novel SPTs to overcome
FQ- and SPT-resistance mutations in gyrase and topoisomerase IV and describe the basis by which mutations
in these enzymes confer resistance to SPTs. This will require similar enzymological activity assays as described
in Specific Aim 1. In addition, I will measure SPT-enzyme binding interactions and conduct competition studies
to determine if resistance mutations affect drug binding and/or placement in the gyrase/topoisomerase IV active
site. Finally, in Specific Aim 3, I will assess the levels and persistence of SPT-stabilized cleavage complexes
generated by gyrase and topoisomerase IV in N. gonorrhoeae cells using an in vivo complex of enzyme bioassay.
These studies have the potential to inform the development of new drugs to overcome antibacterial resistance.
项目总结
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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Jessica A Collins其他文献
Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial.
BIIB080 在阿尔茨海默病中的多次递增剂量研究的探索性 Tau 生物标志物结果:一项随机临床试验。
- DOI:
10.1001/jamaneurol.2023.3861 - 发表时间:
2023 - 期刊:
- 影响因子:29
- 作者:
Amanda Edwards;Jessica A Collins;Candice Junge;Holly Kordasiewicz;Laurence Mignon;Shuang Wu;Yumeng Li;Lin Lin;Jonathan DuBois;R. Hutchison;Nick Ziogas;Melanie Shulman;Laurent Martarello;Danielle Graham;Roger M. Lane;Samantha Budd Haeberlein;John Beaver - 通讯作者:
John Beaver
Jessica A Collins的其他文献
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{{ truncateString('Jessica A Collins', 18)}}的其他基金
TMS in preclinical and prodromal AD: Modulation of brain networks and memory
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9980744 - 财政年份:2019
- 资助金额:
$ 3.3万 - 项目类别:
TMS in preclinical and prodromal AD: Modulation of brain networks and memory
TMS 在临床前和前驱 AD 中的应用:大脑网络和记忆的调节
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9815073 - 财政年份:2019
- 资助金额:
$ 3.3万 - 项目类别:
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