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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：
NEIL OSHEROFF
金额：
$ 66.89万
依托单位：
VANDERBILT UNIVERSITY
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：
https://reporter.nih.gov/project-details/10667862
关键词：
Acinetobacter baumannii Active Sites Amino Acids Anti-Bacterial Agents Aspartic Acid Bacillus anthracis Bacterial Drug Resistance Binding Bypass Cell Death Cell Death Induction Cells Ciprofloxacin Clinical Complex DNA DNA Damage DNA Double Strand Break DNA Maintenance DNA Topoisomerase IV Double Effect Drug Interactions Drug resistance Drug usage Enzyme Inhibition Enzymes Escherichia coli Fluoroquinolones Francisella tularensis Genetic Materials Genome Goals Handedness Health Human In Vitro Incidence Ions Laboratories Libraries Ligation Mediating Metals Monitor Mutation Mycobacterium tuberculosis Neisseria gonorrhoeae Neurofibrillary Tangles New Agents Oral Pharmaceutical Preparations Phase III Clinical Trials Physiological Positioning Attribute Publishing Research Resistance Role Serine Single-Stranded DNA Site Staphylococcus aureus Structure Superhelical DNA System Topoisomerase II Topoisomerase Inhibitors Toxin Water World Health Organization antimicrobial bacterial resistance cellular targeting clinical efficacy drug action fluoroquinolone resistance in vitro activity in vivo member mutant novel pathogen resistance mechanism targeted 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