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.

项目概要 抗生素耐药性的不断上升可能会导致未来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) 仍然是主要病原体。新型抗菌 迫切需要培训课程，以确保针对 MRSA 和其他耐药细菌有足够的治疗选择。 新型细菌 II 型拓扑异构酶抑制剂 (NBTI) 通过针对经过临床验证的细菌发挥功效 必需酶、DNA 旋转酶和拓扑异构酶 IV (TopoIV)。一种新颖的绑定模式避免了基于目标的 与氟喹诺酮类药物的交叉耐药性，并将 NBTI 确立为一种新的抗菌药物。铅，gepotidacin， 即将获得 FDA 批准，多项已完成的 2 期临床试验和正在进行的 3 期临床试验。 已观察到对gepotidacin 的耐药性，但其特征却很差。的变革潜力 NBTI 需要更好地理解作用/耐药机制和新的药物化学 提供高效后续 NBTI 的策略，这是本提案的重点领域。 迄今为止，我们已经合成了超过 250 种高度多样化的 NBTI。我们的抗 MRSA 先导化合物 147 在体内得到了证明 通过合理设计的减少，在两种感染模型中具有功效，并具有良好的心血管安全性 的碱性和亲脂性。我们已经生成了具有改进的旋转酶和 TopoIV 双靶向的 NBTI， 自发耐药率降低，并且比 Gepotidacin 对 NBTI 具有更强的抗菌活性 耐药 MRSA。与gepotidacin 相比，几种新合成的含酰胺的 NBTI 诱导 DNA 我们将研究双链断裂作为 NBTI 类的新作用机制。关键的是，我们 还建议对我们现有的和计划中的 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 解决有关 NBTI 抵抗的出现和战略的主要未解答问题 克服这个问题。总的来说，我们的目标是产生先导化合物作为创新的化学工具和/或临床 进一步发展的候选人。 我们的跨学科团队将追求三个综合的具体目标： 1) 合成结构和机制上不同且具有类药特性的 NBTI 2) 评估新 NBTI 的抗菌活性并鉴定/表征关键 NBTI 抗性金黄色葡萄球菌突变体 3) 阐明新先导 NBTI 的作用机制和分子耐药性 目标 1 作为该提案的创新引擎。目标 2 和 3 通过迭代循环支持目标 1 进行严格的分析以提供新的先导化合物。有关起源的新基本信息， 机制，以及对 NBTI 获得性耐药性的影响/规避将推进这一新类别 抗菌药物是通过解决抗菌药物耐药性危机来促进人类健康的途径。