Mechanistic Studies of Gyrase/Topoisomerase IV-Targeted Antibacterials
旋转酶/拓扑异构酶 IV 靶向抗菌药物的机理研究
基本信息
- 批准号:10667862
- 负责人:
- 金额:$ 66.89万
- 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:2023-03-23 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:Acinetobacter baumanniiActive SitesAmino AcidsAnti-Bacterial AgentsAspartic AcidBacillus anthracisBacterial Drug ResistanceBindingBypassCell DeathCell Death InductionCellsCiprofloxacinClinicalComplexDNADNA DamageDNA Double Strand BreakDNA MaintenanceDNA Topoisomerase IVDouble EffectDrug InteractionsDrug resistanceDrug usageEnzyme InhibitionEnzymesEscherichia coliFluoroquinolonesFrancisella tularensisGenetic MaterialsGenomeGoalsHandednessHealthHumanIn VitroIncidenceIonsLaboratoriesLibrariesLigationMediatingMetalsMonitorMutationMycobacterium tuberculosisNeisseria gonorrhoeaeNeurofibrillary TanglesNew AgentsOralPharmaceutical PreparationsPhase III Clinical TrialsPhysiologicalPositioning AttributePublishingResearchResistanceRoleSerineSingle-Stranded DNASiteStaphylococcus aureusStructureSuperhelical DNASystemTopoisomerase IITopoisomerase InhibitorsToxinWaterWorld Health Organizationantimicrobialbacterial resistancecellular targetingclinical efficacydrug actionfluoroquinolone resistancein vitro activityin vivomembermutantnovelpathogenresistance mechanismtargeted agent
项目摘要
Fluoroquinolones, such as ciprofloxacin, are among the most efficacious and broad-spectrum oral
antibacterials in clinical use. The World Health Organization lists them in their five “Highest Priority Critically
Important Antimicrobials,” and these drugs are the most heavily prescribed antibacterials worldwide.
The cellular targets of fluoroquinolones are the bacterial type II topoisomerases, gyrase and topoisomerase IV.
These essential enzymes regulate DNA under- and overwinding and remove knots and tangles from the genome
by generating transient double-stranded breaks in the genetic material. Fluoroquinolones act by increasing levels
of double-stranded DNA breaks generated by gyrase and topoisomerase IV, which converts these enzymes into
cellular toxins that fragment the genome. Although gyrase and topoisomerase IV are both physiological targets
for fluoroquinolones, their relative importance to drug action appears to be species- and drug-dependent.
There is a growing crisis in antibacterial resistance and fluoroquinolone resistance is becoming prevalent. This
resistance is threatening the clinical efficacy of fluoroquinolones. Initial fluoroquinolone resistance is most often
associated with specific mutations in gyrase and/or topoisomerase IV that occur at a serine residue (originally
described as Ser83 in the GyrA subunit of Escherichia coli gyrase) and a glutamic/aspartic acid residue 4 amino
acids downstream. Based on a published structure and functional studies from the Osheroff laboratory, these
residues are proposed to anchor a water-metal ion bridge that serves as the primary conduit between fluoro-
quinolones and gyrase/topoisomerase IV.
The identification and characterization of novel agents that act against these well-validated enzyme targets
and overcome fluoroquinolone resistance could have important health ramifications. Recently, two new classes
of gyrase/topoisomerase IV-targeted agents have been described that appear to overcome this resistance, Novel
Bacterial Topoisomerase Inhibitors (NBTIs) and Spiropyrimidinetriones (SPTs). Members of these classes,
gepotidacin (NBTI) and zoliflodacin (SPT), have advanced to Phase 3 clinical trials. NBTIs are unique, as they
induce single- rather than double-stranded enzyme-generated DNA breaks. However, little is known about the
actions of NBTIs and SPTs against gyrase/topoisomerase IV or the mechanism of drug resistance.
There is an urgent need to identify drugs that display activity against fluoroquinolone-resistant bacteria. Thus,
the goals of this project are to further define the mechanism of action of fluoroquinolones, NBTIs, and SPTs against
gyrase and topoisomerase IV in vivo and in cells, to characterize the basis of target-mediated drug resistance,
and to identify novel compounds that overcome resistance. Research will benefit from the broad library of wild-
type and drug-resistant gyrase/topoisomerase IV available in the Osheroff laboratory, which includes enzymes
from Bacillus anthracis, E. coli, Staphylococcus aureus, Mycobacterium tuberculosis, Neisseria gonorrhoeae,
Francisella tularensis, and Acinetobacter baumannii. These pathogens have substantial effects on human health.
氟喹诺酮类药物,如环丙沙星,是最有效的广谱口服药物之一
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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NEIL OSHEROFF其他文献
NEIL OSHEROFF的其他文献
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{{ truncateString('NEIL OSHEROFF', 18)}}的其他基金
Mechanistic Studies of Type II Topoisomerases and Topoisomerase-Targeted Agents
II 型拓扑异构酶和拓扑异构酶靶向药物的机理研究
- 批准号:
10364870 - 财政年份:2018
- 资助金额:
$ 66.89万 - 项目类别:
Mechanistic Studies of Type II Topoisomerases and Topoisomerase-Targeted Agents
II 型拓扑异构酶和拓扑异构酶靶向药物的机理研究
- 批准号:
10533336 - 财政年份:2018
- 资助金额:
$ 66.89万 - 项目类别:
Mechanistic Studies of Type II Topoisomerases and Topoisomerase-Targeted Agents
II 型拓扑异构酶和拓扑异构酶靶向药物的机理研究
- 批准号:
10079499 - 财政年份:2018
- 资助金额:
$ 66.89万 - 项目类别:
REGULATION OF CASEIN KINASE II BY EGF IN MAMMALIAN CELLS
哺乳动物细胞中 EGF 对酪蛋白激酶 II 的调节
- 批准号:
6236860 - 财政年份:1996
- 资助金额:
$ 66.89万 - 项目类别:
DNA LESIONS AS ENDOGENOUS TOPOISOMERASE POISONS
DNA 损伤作为内源性拓扑异构酶毒物
- 批准号:
2415346 - 财政年份:1996
- 资助金额:
$ 66.89万 - 项目类别:
DNA LESIONS AS ENDOGENOUS TOPOISOMERASE POISONS
DNA 损伤作为内源性拓扑异构酶毒物
- 批准号:
2910216 - 财政年份:1996
- 资助金额:
$ 66.89万 - 项目类别:
DNA LESIONS AS ENDOGENOUS TOPOISOMERASE POISONS
DNA 损伤作为内源性拓扑异构酶毒物
- 批准号:
6131038 - 财政年份:1996
- 资助金额:
$ 66.89万 - 项目类别:
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