Callyaerins as lead structures and chemical probes for antitubercular drug discovery

尽管一百多年来一直在努力，但结核病仍然是全球健康负担。特别是，耐多药结核病（MDR-TB）甚至广泛耐药结核病（XDR-TB）菌株的增加实际上是目前化疗无法治疗的，这代表了一种需要替代方法的未满足的医疗需求。因此，在本项目中，我们将评估一种有前途的抗结核天然产物化合物类，Callyaerins。Callyaerins是具有罕见的（Z）-2，3-二氨基丙烯酰胺（DAA）部分的环肽，其显示有利的抗结核生长特性以及合适的治疗窗。然而，它们的基本作用方式迄今仍不清楚。通过联合化学生物学的努力，我们将研究这种有前途的化合物类的潜在范围和分子机制。为此，我们将使用化学合成和生物测定来改善Callyaerins的抗结核作用和治疗窗口，并推导其潜在的结构-活性关系。此外，我们将使用化学蛋白质组学和化学遗传学与生物化学方法相结合，以确定和功能特性的直接抗结核目标（S）和结核病的病原体结核分枝杆菌中Callyaerins的分子机制。最后，我们将在相关的TB动物模型中评估Callyaerins。因此，我们的项目将有助于开发替代抗结核化疗的挑战，以及确定可用于对抗结核病的新因素和机制。

Despite intense efforts for now more than a hundred years, tuberculosis (TB) still remains a global health burden. In particular the rise of multidrug-resistant (MDR-TB) and even extensively drug-resistant (XDR-TB) strains that are virtually untreatable by current chemotherapies represents an unmet medical need that requires alternative approaches. In this project, we will therefore evaluate a promising anti-TB natural product compound class, the Callyaerins. Callyaerins are cyclopeptides with a rare (Z)-2,3-diaminoacrylamide (DAA) moiety that display favorable antitubercular growth properties combined with a suitable therapeutic window. Their underlying mode-of-action however remains unknown so far. By a conjoint chemical biology effort, we will thus investigate the potential scope and molecular mechanism of this promising compound class. To this end, we will use chemical synthesis and biological assays to improve the antitubercular effects and therapeutic window of Callyaerins and to deduce their underlying structure-activity relationships. In addition, we will use chemical proteomics and chemical genetics in combination with biochemical approaches to identify and functionally characterize the direct antitubercular target(s) and molecular mechanism of Callyaerins in Mycobacteria tuberculosis, the etiological agent of TB. Finally, we will evaluate the Callyaerins in relevant TB animal models. Our project will thus contribute to the challenge of developing alternative anti-TB chemotherapies as well as to identify novel factors and mechanisms that can be exploited to combat TB.