Overcoming Resistance to Novel Bacterial Topoisomerase Inhibitors

克服对新型细菌拓扑异构酶抑制剂的耐药性

• 批准号: 10567079
• 负责人: Mark J. Mitton-Fry
• 金额: $ 60.23万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-05 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567079
• 关键词: Address; Amides; Amino Acid Substitution; Anti-Bacterial Agents; Antimicrobial Resistance; Area; Bacteria; Binding; Biochemical; Biochemical Pharmacology; Biological; Biological Assay; Cardiovascular system; Cells; Chemicals; Clinical; Collection; Coupled; DNA; DNA Damage; DNA Double Strand Break; DNA Gyrase; DNA Topoisomerase IV; Development; Drug Targeting; Ensure; Enzyme Inhibition; Enzymes; Evaluation; Exhibits; Genus staphylococcus; Goals; Growth; Health; Human; In Vitro; Infection; Kinetics; Knowledge; Label; Lead; Measures; Metabolism; Methicillin Resistance; Microbiology; Minimum Inhibitory Concentration measurement; Modeling; Modification; Molecular; Multi-Drug Resistance; Mutation; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phase III Clinical Trials; Point Mutation; Positioning Attribute; Property; Refractory; Resistance; Resistance development; Resistance profile; Risk; Roentgen Rays; SOS Response; Safety; Series; Staphylococcus aureus; Structural Models; Structure; Therapeutic; Time; Topoisomerase Inhibitors; Topoisomerase-II Inhibitor; alkalinity; analog; bacterial resistance; clinical candidate; clinical development; computational chemistry; design; drug resistant bacteria; fitness; fluoroquinolone resistance; improved; in vivo; inhibitor; inhibitor therapy; innovation; insight; lead candidate; lipophilicity; methicillin resistant Staphylococcus aureus; molecular dynamics; mortality; multidisciplinary; mutant; novel; pathogen; phase II trial; rational design; resistance frequency; resistance mutation; resistant strain; structural biology; success; tool

PROJECT SUMMARY The rising tide of antimicrobial resistance threatens catastrophic increases in mortality in the coming decades. Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading pathogen. New antibacterial classes are urgently needed to ensure adequate therapeutic options for MRSA and other resistant bacteria. Novel Bacterial Type II Topoisomerase Inhibitors (NBTIs) derive their efficacy by targeting the clinically validated essential enzymes, DNA gyrase and topoisomerase IV (TopoIV). A novel binding mode avoids target-based cross-resistance to fluoroquinolones and establishes NBTIs as a new antibacterial class. A lead, gepotidacin, stands at the threshold of FDA approval, with several completed Phase 2 and ongoing Phase 3 clinical trials. Resistance to gepotidacin has been observed but is very poorly characterized. The transformative potential of the NBTIs will require a better understanding of mechanisms of action/resistance and new medicinal chemistry strategies to deliver highly efficacious successor NBTIs, the areas of focus in the present proposal. To date, we have synthesized >250 highly diverse NBTIs. Our anti-MRSA lead, 147, showed in vivo efficacy in two infection models and a favorable cardiovascular safety profile by rationally designed reductions of basicity and lipophilicity. We have generated NBTIs with improved dual-targeting of gyrase and TopoIV, reduced rates of spontaneous resistance, and greater antibacterial activity over gepotidacin against NBTI- resistant MRSA. In contrast to gepotidacin, several newly synthesized amide-containing NBTIs induced DNA double strand breaks which we will investigate as a new mechanism of action for the NBTI class. Critically, we also propose that studies with our existing and planned NBTIs, coupled with our demonstrated expertise in microbiology, biochemical pharmacology, computational chemistry, and structural biology, will effectively address major unanswered questions regarding the emergence of resistance to NBTIs and strategies to overcome this issue. Overall, our goal is to generate lead compounds as innovative chemical tools and/or clinical candidates for further development. Three integrated specific aims will be pursued by our interdisciplinary team to: 1) Synthesize structurally and mechanistically distinct NBTIs with druglike properties 2) Evaluate new NBTIs for antibacterial activity & identify/characterize key NBTI-resistant S. aureus mutants 3) Elucidate the mechanism(s) of action of and molecular resistance to new lead NBTIs Aim 1 serves as the innovation engine for the proposal. Aims 2 and 3 support Aim 1 through iterative cycles of rigorous assays to provide new lead compounds. New fundamental information concerning the origin, mechanism, and impact/circumvention of acquired resistance to NBTIs will advance this new class of antibacterials as a pathway to promote human health by addressing the crisis in antimicrobial resistance.

项目摘要 抗菌抗性的上升潮流威胁到即将到来的死亡率的灾难性增加 几十年。耐甲氧西林金黄色葡萄球菌（MRSA）仍然是领先的病原体。新抗菌 迫切需要类别以确保MRSA和其他耐药细菌的足够治疗选择。 新型细菌II型拓扑异构酶抑制剂（NBTIS）通过靶向临床验证来提高其功效 必需酶，DNA陀螺酶和拓扑异构酶IV（topoiv）。一种新颖的绑定模式避免了基于目标的绑定模式 对氟喹诺酮类的抗性，并将NBTIS建立为新的抗菌类别。铅，gepotidacin， 位于FDA批准的门槛上，有几个完整的第2阶段和正在进行的3阶段临床试验。 已经观察到了对吉普迪拉辛的抗性，但表征的特征很差。的变革潜力 NBTI将需要更好地理解动作/抗药性机制和新药物的化学机制 提供高效的继任者NBTI的策略，即本提案的重点领域。 迄今为止，我们的合成> 250个高度多样化的NBTI。我们的抗MRSA铅147在体内显示 通过合理设计的降低，在两个感染模型和有利的心血管安全性方面的功效 碱性和亲脂性。我们已经产生了NBTI，并改善了Gyrase和topoiv的双重目标， 降低自发性抗性的速率，而抗菌素比gepotidacin降低了NBTI-的抗菌活性 抵抗MRSA。与Gepotidacin相反，几种新合成的含酰胺的NBTI诱导的DNA 双链断裂，我们将作为NBTI类的新作用机理进行调查。批判性，我们 还建议对我们现有和计划的NBTI进行研究，再加上我们在 微生物学，生化药理学，计算化学和结构生物学将有效地有效 解决有关对NBTIS抵抗的出现和战略的主要问题的问题 克服这个问题。总体而言，我们的目标是作为创新的化学工具和/或临床生成铅化合物 候选人进一步发展。 我们的跨学科团队将追求三个综合目标： 1）与药物样性质合成结构和机械上不同的NBTI 2）评估新的NBTI用于抗菌活性并识别/表征耐NBTi的金黄色葡萄球菌突变体 3）阐明对新铅NBTI的作用和分子抗性的机制 AIM 1是该提案的创新引擎。目标2和3支持目标1通过迭代周期 严格的测定法以提供新的铅化合物。有关起源的新基本信息， 机制以及对NBTI的抗药性的影响/规避将推进这一新类别 通过解决抗菌抗性危机，抗菌作为促进人类健康的途径。