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,如环丙沙星,是最有效和广谱的口服给药途径之一。
抗菌药物在临床上的应用世界卫生组织将其列为五个“最高优先级
重要的抗菌药物”,这些药物是世界上最常用的抗菌药物。
氟喹诺酮类药物的细胞靶点是细菌II型拓扑异构酶、促旋酶和拓扑异构酶IV。
这些必需的酶调节DNA的欠缠绕和过缠绕,并从基因组中去除结和缠结
通过在遗传物质中产生短暂的双链断裂。氟喹诺酮类药物通过增加
由促旋酶和拓扑异构酶IV产生的双链DNA断裂,将这些酶转化为
分裂基因组的细胞毒素虽然促旋酶和拓扑异构酶IV都是生理靶点,
对于氟喹诺酮类药物,它们对药物作用的相对重要性似乎是种属和药物依赖性的。
抗菌药物耐药危机日益严重,氟喹诺酮类药物耐药现象日益普遍。这
耐药性威胁着氟喹诺酮类药物的临床疗效。最初的氟喹诺酮类耐药最常见于
与发生在丝氨酸残基(最初是丝氨酸残基)的促旋酶和/或拓扑异构酶IV中的特定突变相关
描述为大肠杆菌促旋酶的GyrA亚基中的Ser 83)和谷氨酸/天冬氨酸残基4个氨基酸
酸下游根据Osheroff实验室发表的结构和功能研究,这些
残基被提议用于锚水-金属离子桥,该离子桥用作氟-
喹诺酮类和促旋酶/拓扑异构酶IV。
鉴定和表征针对这些经过充分验证的酶靶点的新型药物
并克服氟喹诺酮耐药性可能对健康产生重要影响。最近,两个新班级
已经描述了旋转酶/拓扑异构酶IV靶向剂的组合物,其似乎克服了这种耐药性,
细菌拓扑异构酶抑制剂(NBTI)和螺嘧啶三酮(SPT)。这些阶级的成员,
Gepotidacin(NBTI)和zoliflodacin(SPT)已进入3期临床试验。NBTI是独一无二的,因为它们
诱导单链而不是双链酶产生DNA断裂。然而,人们对此知之甚少。
NBTI和SPT对促旋酶/拓扑异构酶IV的作用或耐药机制。
迫切需要鉴定对氟喹诺酮耐药细菌显示活性的药物。因此,在本发明中,
本项目的目标是进一步确定氟喹诺酮类、NBTI和SPT的作用机制,
促旋酶和拓扑异构酶IV在体内和细胞中的作用,以表征靶介导的耐药性的基础,
并鉴定克服耐药性的新化合物。研究将受益于广泛的野生图书馆-
型和耐药促旋酶/拓扑异构酶IV,其包括酶
从炭疽芽孢杆菌(Bacillus anthracis)、E.大肠杆菌,金黄色葡萄球菌,结核分枝杆菌,淋病奈瑟菌,
土拉热弗朗西斯菌和鲍曼不动杆菌。这些病原体对人类健康有重大影响。
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:
6386305 - 财政年份:1996
- 资助金额:
$ 66.89万 - 项目类别:
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