Exploratory Chemistry on a new antibiotic

本项目研究新发现的抗生素的构效关系 Teixobactin，目标是提供一个比母公司更具发展优势的候选人 化合物。Teixobactin是一种不寻常的脱脂肽，是一类新的肽聚糖的第一个成员。 合成抑制剂。Teixobactin针对脂类II，即肽聚糖前体，以及脂类III，即磷壁酸前体。它 结合到十一碳烯基-PP-糖，这是未知的修饰，而不是较晚的脂质II-d-Ala-d-Ala 万古霉素靶向的可修饰形式。这种独特的行动模式，绑定到两个目标，这两个目标都不是 一种蛋白质，表明抗药性将很难产生。到目前为止，还没有检测到耐药性。 Teixobactin对多种革兰氏阳性菌有较强的抗菌活性，包括金黄色葡萄球菌、金黄色葡萄球菌、金黄色葡萄球菌和金黄色葡萄球菌。 肺炎、炭疽杆菌、结核分枝杆菌、粪肠球菌和粪肠球菌。它能有效地抵抗抵抗形式的 这些病原体包括对万古霉素耐药的肠球菌。替考巴汀对小鼠有很高的疗效 MRSA败血症和大腿感染模型，以及在肺部感染模型中对抗肺炎链球菌。 Teixobactin本身也在进入开发阶段。然而，对替克生的研究已经发现了一种 可以改进的化合物的性能。替考巴汀有在血清中凝胶化的趋势，这可能 出现问题取决于人类所需的给药方案(例如，如果较高的血清浓度 人类比老鼠更需要这种药物)，并在给药方面提出了挑战 在临床前研究中使用较高剂量。小肽的凝胶是一种众所周知的现象，它已经被 成功解决了药物化学优化问题。我们将开展药物化学运动 为了更好地了解分子的SAR，并利用这些信息来产生类似物 不是凝胶，但保留了强大的抗菌特性。早期、主动地了解替科巴汀的SAR 还将指导新模拟的设计，以解决在 替克生本身的发展。 将对修饰分子中的各种位置的效果进行评估， 通过半合成和全合成两种方法。已经生产了几个类似的产品 这两种方法都证明了该方法的可行性。将生产多个类似物，并 经抗菌活性、脂类II结合、凝胶化和体外粘合性能测试。与以下三个类似 凝胶减少但体外性能良好的将被选用于小鼠研究，包括MTD、PK和 在大腿感染模型中对抗MRSA的疗效。这一项目的结果将产生一种治疗作用 候选人准备进入进一步的发展，包括支持IND的学习。

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.