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 抗生素耐药性的上升趋势威胁着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）仍然是主要的病原体。新型抗菌 因此，迫切需要对耐甲氧西林金黄色葡萄球菌（MRSA）和其他耐药细菌进行分类，以确保有足够的治疗选择。 新型细菌II型拓扑异构酶抑制剂（NBTI）通过靶向临床验证的 必需酶，DNA促旋酶和拓扑异构酶IV（TopoIV）。一种新的绑定模式避免了基于目标的 交叉耐药性的氟喹诺酮类药物，并建立NBTI作为一个新的抗菌类。一种铅，吉泊替辛， 站在FDA批准的门槛上，有几个完成的2期和正在进行的3期临床试验。 已观察到对吉泊替辛的耐药性，但表征非常差。的变革潜力 非细菌性感染需要更好地理解作用/耐药性机制和新的药物化学 战略，以提供高度有效的后续NBTI，在本建议的重点领域。 迄今为止，我们已经合成了>250种高度多样化的NBTI。我们的抗耐甲氧西林金黄色葡萄球菌铅，147，显示在体内 通过合理设计的减量，在两种感染模型中的有效性和有利的心血管安全性特征 碱性和亲脂性。我们已经产生了具有改进的促旋酶和TopoIV双重靶向的NBTI， 自发耐药率降低，对NBTI的抗菌活性高于吉泊替辛， 耐药MRSA。与吉泊替辛相反，几种新合成的含酰胺的NBTI诱导DNA 双链断裂，我们将其作为NBTI类的新作用机制进行研究。关键是，我们 我还建议与我们现有的和计划中的NBTI进行研究，再加上我们在以下方面的专业知识： 微生物学、生化药理学、计算化学和结构生物学，将有效地 解决有关出现对非生物技术倡议的耐药性的重大未决问题， 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/或临床应用。 候选人进一步发展。 我们的跨学科团队将追求三个综合的具体目标： 1)合成具有药物样性质的结构和机制不同的NBTI 2)评估新的NBTI的抗菌活性并识别/表征关键的NBTI耐药S。金黄色葡萄球菌突变株 3)阐明新型先导NBTI的作用机制和分子耐药性 目标1是提案的创新引擎。目标2和3通过迭代循环支持目标1 严格的实验来提供新的先导化合物。关于起源的新的基本信息， 机制，以及对NBTI获得性抗性的影响/规避将促进这种新类型的 抗菌药物是通过解决抗菌素耐药性危机促进人类健康的途径。