Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens

针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂

• 批准号: 10563142
• 负责人: Ambrose Lin Yau Cheung
• 金额: $ 79.94万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563142
• 关键词: Affinity Chromatography; Animal Model; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Bacteria; Binding; Binding Proteins; Biological Assay; Cells; Daptomycin; Data; Defect; Derivation procedure; Drug Kinetics; Dyes; Electron Microscopy; Endocarditis; Ensure; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Evaluation Studies; Exhibits; Frequencies; Genetic; Genomics; Goals; Gram-Positive Bacteria; Hospitals; In Vitro; Infection; Infection Control; Infectious Skin Diseases; Infective endocarditis; Lead; Length of Stay; Libraries; Linezolid; Lipid Bilayers; Lipids; Mass Spectrum Analysis; Measures; Medicine; Membrane; Microsomes; Minnesota; Modeling; Modification; Molecular; Multi-Drug Resistance; Mus; Mutation; New Agents; Nosocomial Infections; Organism; Oryctolagus cuniculus; Pathogenicity; Pharmaceutical Preparations; Plasma Proteins; Positioning Attribute; Procedures; Property; Proteomics; Public Health; Publishing; Quinazolines; Quinolones; Research; Resistance; Safety; Series; Serum; Solubility; Specificity; Staphylococcus aureus infection; Staphylococcus epidermidis; Streptococcus pneumoniae; Structure; Structure-Activity Relationship; Toxic effect; Universities; Vancomycin; Work; activity-based protein profiling; analog; aqueous; bactericide; biochemical tools; biophysical tools; carbonyl group; crosslink; cytotoxicity; design; drug development; drug discovery; drug disposition; efficacy evaluation; efficacy study; improved; in vivo; lipophilicity; medical schools; methicillin resistant Staphylococcus aureus; mutant; novel; pathogen; quinoline; scaffold; screening; simulation

Abstract Infections due to resistant Gram+ organisms are on the rise, likely due to a variety of factors including longer hospital stay, increased frequency of invasive procedures and pervasive antibiotic therapy. Compounding the problem is the emergence of multi-drug resistance (MDR) among many Gram+ pathogens (MRSA, S. epidermidis, Enterococcus and S. pneumoniae). Despite antibiotic stewardship and infection control, new agents against these Gram+ pathogens are urgently needed. After screening a ~60,000 preselected compound library, we obtained DNAC-2, a 4-hydroxyquinoline derivative, that exhibited antibacterial activities against MRSA and Enterococcus. We subsequently synthesized 3 series of analogues involving over 50 compounds. Two of these analogues in the 2th series, JRS-3-56 (compound 1) and JRS-4-32 (compound 2), were cidal against MRSA, S. epidermidis, E. faecalis and E. faecium, with MIC ≤0.2 μg/ml. However, both 1 and 2 have poor predicted aqueous solubility with high cLogP (7.7 and 6.0, respectively). Conversion of quinoline to quinazoline for 1 improved the cLogP (from 6.06 to 5.08) but led to a slight increase in MIC (0.25 to 2 µg/ml). In the latest series, we introduced a carbonyl group at C-4 and a C to N substitution at the C-1 position, yielding compounds 3 and 4 with low cLogPs and very low MIC (0.06 µg/ml for USA300), accompanied by a much tighter SAR. Using macromolecular synthesis assays, membrane-specific dye FM4- 64 and electron microscopy studies, we have evidence that 1 and 2 target the Gram+ membrane (3 and 4 also resulted in membrane defect as detected by the FM4-64 dye), but not Gram- or eukaryotic membrane, thus implying some degree of specificity. However, the exact target of these compounds which likely differs from daptomycin, is not known. In this application, we seek to define the mechanism of action of these quinoline/quinolone derivatives and further explore the SAR that governs in vitro and in vivo activities and drug disposition properties. Accordingly, we have the following specific aims: 1) design and synthesize quinoline/quinolone derivates by defining the SAR that governs activity against major Gram+ pathogens and drug disposition properties (MIC, solubility, overt toxicity and serum binding etc.); 2) delineate the mechanism of action of the quinoline/quinolone derivatives with genetic, biochemical and biophysical tools; 3) pharmacokinetic and efficacy studies where candidates compounds will be evaluated for their drug disposition properties to ensure safety and selectivity followed by selection of “lead” compounds for full PK evaluation and efficacy studies with two animal models. The goal of these studies is to identify “druggable membrane-active compounds” with broad Gram+ activity. If successful, we believe these compounds will represent a new class of membrane-active compounds that offer a significant advance in drug development.

抽象的 由于抗性革兰氏+生物引起的感染正在增加，这可能是由于多种因素所致 住院住院，侵入性手术的频率增加和普遍存在的抗生素疗法。复合 问题在于许多革兰氏病原体中多药耐药性（MDR）的出现（MRSA，S。 尽管抗生素管理和感染控制，但 迫切需要针对这些革兰氏+病原体的药物。筛选约60,000次预览后 复合库，我们获得了一种暴露于抗菌活性的4-羟基喹啉衍生物DNAC-2 反对MRSA和肠球菌。随后，我们合成了3个涉及50多个类似物 化合物。第2系列中的两个类似物JRS-3-56（化合物1）和JRS-4-32（化合物2）， 是针对MRSA，S。表皮，大肠杆菌和E.粪的CIDAL，MIC≤0.2μg/ml。但是，两个都1 和2的较差的预测水溶液具有高clOGP（分别为7.7和6.0）。转换 喹啉至喹唑啉1的1改进了clogp（从6.06到5.08），但导致麦克风略有增加（0.25 （至2 µg/ml）。在最新系列中，我们在C-4引入了一个Carbonyl组，并在C-1替换了N 位置，具有低堵塞和非常低的MIC（USA300的0.06 µg/ml）的化合物3和4，， 伴随着更紧密的SAR。使用大分子合成测定法，膜特异性染料FM4- 64和电子显微镜研究，我们有证据表明1和2靶向革兰氏+膜（3和4 还导致膜缺陷，如FM4-64染料所检测到的，但没有革兰氏阴性膜或真核膜 因此意味着一定程度的特异性。但是，这些化合物的确切靶标可能会有所不同 来自Daptomycin，尚不清楚。在此应用中，我们试图定义这些行动的机制 喹啉/喹诺酮衍生物，并进一步探索在体外和体内活动的SAR和 药物处置特性。彼此之间，我们有以下特定目的：1）设计和合成 喹啉/喹诺酮衍生 药物处置特性（MIC，溶解度，明显的毒性和血清结合等）； 2）描述机制 喹啉/喹啉衍生物具有遗传，生化和生物物理工具的作用； 3） 药代动力学和效率研究，将评估候选化合物的药物 处置属性以确保安全性和选择性，然后选择完整PK的“铅”化合物 评估和有效研究两个动物模型。这些研究的目的是确定“可药物 具有广泛革兰氏+活性的膜活性化合物。如果成功，我们相信这些化合物将会 代表一类新的膜活性化合物，可在药物开发方面有重大进步。