Novel Bacterial Topoisomerase Inhibitors Targeting Gram-Negative Bacteria

针对革兰氏阴性菌的新型细菌拓扑异构酶抑制剂

• 批准号: 10242615
• 负责人: Mark J. Mitton-Fry
• 金额: $ 19.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242615
• 关键词: Acinetobacter baumannii; Address; Amines; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Aspartate; Attention; Attenuated; Automobile Driving; Bacteria; Binding; Biological; Biological Assay; Cardiovascular system; Cells; Chemicals; Clinical; Clinical Trials; DNA Gyrase; DNA Topoisomerase IV; Development; Dioxanes; Enzyme Inhibition; Enzymes; Escherichia coli; Evaluation; Fluoroquinolones; Frequencies; Goals; Gram-Negative Bacteria; Health; Human; Infection; Lead; Link; Measures; Minimum Inhibitory Concentration measurement; Modification; Molecular; Molecular Conformation; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Penetration; Property; Pseudomonas aeruginosa; Reporting; Research; Resistance; Safety; Series; Societies; Structure; Testing; Therapeutic Index; Topoisomerase; Topoisomerase Inhibitors; Topoisomerase-II Inhibitor; Translating; World Health Organization; alkalinity; base; chemical synthesis; clinically relevant; design; drug resistant bacteria; flexibility; fluoroquinolone resistance; improved; inhibitor/antagonist; innovation; methicillin resistant Staphylococcus aureus; novel; pathogen; pathogenic bacteria; pharmacophore; preservation; prospective; screening

PROJECT SUMMARY Antimicrobial resistance, especially in Gram-negative bacterial pathogens, constitutes an urgent threat to human health. The discovery and development of new chemical matter inhibiting essential bacterial targets constitutes one powerful approach to addressing this issue. Novel Bacterial Type II Topoisomerase Inhibitors (NBTIs) derive their antibacterial activity from inhibition of the clinically validated enzymes DNA gyrase and topoisomerase IV (TopoIV). A novel binding mode that obviates target-based cross-resistance to fluoroquinolones has established NBTIs as a new class of antibiotics. However, the ultimate potential of the NBTI class to treat infections caused by Gram-negative pathogens has been limited by cardiovascular safety concerns as well as by the intrinsic challenges of achieving high intracellular concentrations in Gram-negative bacteria. This proposal elaborates strategies to address these key issues that have limited the advancement of the field. We have previously synthesized innovative dioxane-linked NBTIs directed at Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus. Broad spectrum antibacterial screening revealed that representative compounds also possess promising activity against Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. These rationally-designed inhibitors also demonstrate attenuated hERG inhibition as compared to structure-matched controls, offering the promise of improved cardiovascular safety. In this proposal, we hypothesize that the incorporation of specific molecular features, such as a primary amine and reduced conformational flexibility, will enable further improvements in Gram-negative antibacterial activity while preserving a favorable safety profile. We will determine minimum inhibitory concentrations (MICs) and enzymatic (gyrase and TopoIV) IC50 values from a panel of relevant Gram-negative bacteria (P. aeruginosa, A. baumannii, and E. coli). We will utilize our synthetic expertise to interrogate this hypothesis using multiple chemical series, one involving direct modification of our earlier NBTIs and one targeting a restructured NBTI pharmacophore. Our interdisciplinary team will rigorously test these hypotheses according to the following specific aims: 1) Optimize dioxane-linked NBTIs for Gram-negative activity a. Incorporate a primary amine b. Reduce conformational flexibility 2) Redesign NBTI enzyme-binding moiety to incorporate a primary amine 3) Quantify potency with enzymes and cells; measure hERG inhibition Successfully achieving our aims will deliver NBTI lead molecules with enhanced safety and whole cell antibacterial activity against critically important Gram-negative pathogens.

项目摘要 抗菌素耐药性，尤其是在革兰氏阴性细菌病原体中，构成紧急威胁 对人类健康。新化学物质的发现和开发抑制了基本细菌靶标 构成了解决此问题的一种有力方法。新型细菌II型拓扑异构酶抑制剂 （NBTIS）从抑制临床验证的酶DNA回酶和 拓扑异构酶IV（topoiv）。一种新型的结合模式，该模式避免了基于目标的交叉抗性 Fluoroquinolones已将NBTIS建立为新的抗生素。但是，NBTI的最终潜力 革兰氏阴性病原体引起的感染的课程受到心血管安全问题的限制 以及通过在革兰氏阴性细菌中实现高细胞内浓度的内在挑战。 该提议阐述了解决这些关键问题的策略，这些问题限制了该领域的进步。 我们以前已经合成了针对革兰氏阳性病原体的创新二恶英连接的NBTI 例如耐甲氧西林金黄色葡萄球菌。广谱抗菌筛查表明 代表性化合物还具有针对革兰氏阴性细菌的有希望的活性 铜绿假单胞菌和鲍曼尼杆菌。这些理性设计的抑制剂也证明了 与结构匹配的对照相比，HERG抑制作用减弱，提供了改善的承诺 心血管安全。在此提案中，我们假设结合了特定的分子特征，例如 作为主要胺和降低构象的柔韧性，将能够进一步改善革兰氏阴性 抗菌活性，同时保留有利的安全性。我们将确定最小抑制 浓度（MIC）和酶促（Gyrase和topoiv）IC50值 细菌（铜绿假单胞菌，A。Baumannii和大肠杆菌）。我们将利用我们的综合专业知识来询问这一点 假设使用多个化学系列，一个涉及直接修改我们的早期NBTI和一个靶向 重组的NBTI药效团。 我们的跨学科团队将根据以下特定目的严格检验这些假设： 1）优化二氧烷连接的NBTI用于革兰氏阴性活动 一个。掺入初级胺 b。降低构象柔韧性 2）重新设计NBTI酶结合部分以掺入初级胺 3）用酶和细胞定量效力；测量HERG抑制作用 成功实现我们的目标将使NBTI铅分子具有增强的安全性和全细胞 针对至关重要的革兰氏阴性病原体的抗菌活性。

项目成果

Novel bacterial topoisomerase inhibitors: unique targeting activities of amide enzyme-binding motifs for tricyclic analogs.

新型细菌拓扑异构酶抑制剂：酰胺酶结合基序对三环类似物的独特靶向活性。

• DOI: 10.1128/aac.00482-23
• 发表时间: 2023
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Mann,ChelseaA;CarvajalMoreno,JessikaJ;Lu,Yanran;Dellos-Nolan,Sheri;Wozniak,DanielJ;Yalowich,JackC;Mitton-Fry,MarkJ
• 通讯作者: Mitton-Fry,MarkJ

Aryl Methyl Ketones: Versatile Synthons in the Synthesis of Heterocyclic Compounds.

• DOI: 10.1055/a-1826-2852
• 发表时间: 2022-06
• 期刊: SynOpen (2017)