Exploratory Chemistry on a new antibiotic

新型抗生素的探索化学

• 批准号: 9294978
• 负责人: Dallas Hughes
• 金额: $ 73.84万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-16 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294978
• 关键词: Address; Anti-Bacterial Agents; Antibiotics; Bacillus anthracis; Bacteria; Binding; Chemistry; Defensins; Depsipeptides; Development; Disasters; Dose; Drug Kinetics; Drug resistance; Enterococcus faecalis; Enterococcus faecium; Evaluation; Glycopeptides; Goals; Gram-Positive Bacteria; Human; In Vitro; Infection; Lead; Lipid III; Lipids; Lung; Maximum Tolerated Dose; Modeling; Modification; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Parents; Peptides; Peptidoglycan; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Property; Proteins; Public Health; Regimen; Resistance; Septicemia; Serum; Site; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Structure-Activity Relationship; Teichoic Acids; Testing; Therapeutic; Thigh structure; Time; United States; Vancomycin; Vancomycin resistant enterococcus; Work; analog; bactericide; combat; cytotoxicity; design; efficacy study; improved; in vitro testing; in vivo; inhibitor/antagonist; member; methicillin resistant Staphylococcus aureus; mouse model; novel; pathogen; phenylalanine methyl ester; preclinical study; sugar; Address; Anti-Bacterial Agents; Antibiotics; Bacillus anthracis; Bacteria; Binding; Chemistry; Defensins; Depsipeptides; Development; Disasters; Dose; Drug Kinetics; Drug resistance; Enterococcus faecalis; Enterococcus faecium; Evaluation; Glycopeptides; Goals; Gram-Positive Bacteria; Human; In Vitro; Infection; Lead; Lipid III; Lipids; Lung; Maximum Tolerated Dose; Modeling; Modification; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Parents; Peptides; Peptidoglycan; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Property; Proteins; Public Health; Regimen; Resistance; Septicemia; Serum; Site; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Structure-Activity Relationship; Teichoic Acids; Testing; Therapeutic; Thigh structure; Time; United States; Vancomycin; Vancomycin resistant enterococcus; Work; analog; bactericide; combat; cytotoxicity; design; efficacy study; improved; in vitro testing; in vivo; inhibitor/antagonist; member; methicillin resistant Staphylococcus aureus; mouse model; novel; pathogen; phenylalanine methyl ester; preclinical study; sugar

This project studies the structure-activity relationship (SAR) of the newly discovered antibiotic teixobactin, with the goal of delivering a candidate that has development advantages over the parent compound. Teixobactin is an unusual depsipeptide that is the first member of a novel class of peptidoglycan synthesis inhibitors. Teixobactin targets lipid II, peptidoglycan precursor, and lipid III, teichoic acid precursor. It binds to undecaprenyl-PP-sugars, which are not known to be modified, as opposed to a later lipid II-d-ala-d-ala modifiable form targeted by vancomycin. This unique mode of action, binding to two targets, neither of which is a protein, suggests that resistance will be very difficult to develop. To date, no resistance has been detected. Teixobactin has potent activity against a broad range of Gram-positive bacteria - S. aureus MRSA, S. pneumoniae, B. anthracis, M. tuberculosis, E. faecalis and E. faecium. It is active against resistant forms of these pathogens, including vancomycin-resistant enterococci. Teixobactin was highly efficacious in a murine MRSA septicemia and thigh infection models, and against S. pneumoniae in a lung infection model. Teixobactin itself is moving into development. However, studies of teixobactin have identified a property of the compound that can be improved. Teixobactin has a tendency to gelate in serum, which may present a problem depending on the dosing regimen required for humans (e.g., if higher serum concentrations of the drug are required for humans than mice), and has presented a challenge in administering the compound at higher doses in preclinical studies. Gelation of small peptides is a well-known phenomenon that has been successfully addressed with medicinal chemistry optimization. We will conduct a medicinal chemistry campaign to gain a good understanding of the SAR of the molecule, and use this information to produce analogs that do not gelate but retain potent antibacterial properties. Early, proactive understanding of the SAR of teixobactin would also guide the design of new analogs that could address additional issues that may come up during the development of teixobactin itself. An evaluation of the effect of modifying a variety of positions in the molecule will be conducted, through both semisynthetic and fully synthetic approaches. Several analogs have already been produced by both approaches, which demonstrate the feasibility of the approach. Multiple analogs will be produced and tested for antibacterial activity, lipid II binding, gelation, and in vitro ADMET properties. Three analogs with reduced gelation but favorable in vitro properties will be selected for mouse studies including MTD, PK, and efficacy against MRSA in the thigh infection model. The results of this project will produce a therapeutic lead candidate ready to enter further development including IND-enabling studies.

该项目研究了新发现的抗生素的结构活性关系（SAR） Teixobactin，目的是提供与父母具有发展优势的候选人 化合物。 Teixobactin是一种不寻常的深度肽，是新型肽聚糖类的第一个成员 合成抑制剂。 Teixobactin靶向脂质II，肽聚糖前体和脂质III，Teichoic酸前体。它 与未知未经修饰的非依赖肾上腺pp的结合，而不是稍后的脂质II-D-ALA-D-ALA 万古霉素针对的可修改形式。这种独特的作用方式，与两个目标结合，这两个目标都不是 一种蛋白质表明耐药性将很难发展。迄今为止，尚未检测到阻力。 Teixobactin具有对各种革兰氏阳性细菌的有效活性-S。金黄色葡萄球菌MRSA，S。 肺炎，B。Nthracis，M。Tolberculosis，E。Faecalis和E.粪便。它具有抗性形式 这些病原体，包括抗性霉素的肠球菌。 Teixobactin在鼠中高效 MRSA败血症和大腿感染模型，以及肺部感染模型中的肺炎链球菌。 Teixobactin本身正在发展。但是，Teixobactin的研究已经确定 可以改进的化合物的属性。 Teixobactin倾向于在血清中凝胶化，这可能 根据人类所需的给药方案提出问题（例如，如果血清浓度较高 人类需要的药物比小鼠需要的，并且在给药化合物方面提出了挑战 在临床前研究中，较高剂量。小肽的凝胶化是一种众所周知的现象 通过药物化学优化成功解决。我们将进行药物化学运动 为了很好地了解分子的SAR，并使用此信息产生类似物 不是凝胶，而是保留有效的抗菌特性。早期，积极地理解Teixobactin的SAR 还将指导设计新类似物的设计，这些模拟可以解决可能在此期间出现的其他问题 Teixobactin本身的发展。 将评估修改分子中各种位置的效果， 通过半合成和完全合成的方法。已经产生了几个类似物 两种方法都证明了方法的可行性。将产生多种类似物，并且 测试了抗菌活性，脂质II结合，凝胶化和体外ADMET特性的测试。三个类似物 凝胶化降低，但将选择在包括MTD，PK和 大腿感染模型中对MRSA的功效。该项目的结果将产生治疗铅 候选人准备进入进一步的发展，包括辅助研究。