Exploratory Chemistry on a new antibiotic

本项目研究了新发现的抗生素的构效关系（SAR） teixobactin，目的是提供一个候选人，具有发展优势，超过父母 化合物. Teixobactin是一种不寻常的缩肽，是一类新的肽聚糖的第一个成员 合成抑制剂Teixobactin靶向脂质II（肽聚糖前体）和脂质III（磷壁酸前体）。它 结合十一异戊二烯基-PP-糖，其不被修饰，与后来的脂质II-d-ala-d-ala相反 万古霉素靶向的修饰形式。这种独特的作用模式，结合两个目标，其中没有一个是 一种蛋白质，表明抵抗力很难产生。迄今为止，尚未发现任何抵抗。 Teixobactin对多种革兰氏阳性菌- S.金黄色葡萄球菌MRSA、S. 肺炎克雷伯氏菌（B. pneumoniae）、B.炭疽菌、M. tuberculosis，E. faecalis和E.屎室它是积极的抵抗形式， 这些病原体，包括万古霉素耐药肠球菌。Teixobactin在小鼠中高度有效， MRSA败血症和大腿感染模型，并针对S。肺炎在肺部感染模型。 Teixobactin本身正在进入开发阶段。然而，teixobactin的研究已经确定了一种 可以改进的化合物的性质。Teixobactin有在血清中胶凝的倾向，这可能 存在依赖于人类所需的给药方案的问题（例如，如果血清浓度较高， 人类比小鼠需要更多的药物），并且在施用该化合物方面提出了挑战 在临床前研究中使用更高剂量。小肽的甘氨酰化是一种众所周知的现象， 通过药物化学优化成功解决。我们将开展一场药物化学运动 为了更好地了解分子的SAR，并利用这些信息来生产类似物， 不会凝胶化，但保留了有效的抗菌性能。早期、主动地了解teixobactin的SAR 还将指导新的类似物的设计，这些类似物可以解决在开发过程中可能出现的其他问题。 Teixobactin本身的发展。 将对修饰分子中各种位置的效果进行评价， 通过半合成和全合成的方法。几种类似物已经由 这两种方法，证明了该方法的可行性。将产生多种类似物， 测试抗菌活性、脂质II结合、凝胶化和体外ADMET性质。三种类似物， 将选择降低的胶凝但有利的体外性质用于小鼠研究，包括MTD、PK和 在大腿感染模型中对抗MRSA的功效。这个项目的结果将产生一个治疗铅 候选人准备进入进一步发展，包括IND使能研究。

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.