Callyaerins as lead structures and chemical probes for antitubercular drug discovery

尽管一百多年来作出了巨大努力，结核病仍然是一个全球卫生负担。特别是当前化疗几乎无法治疗的耐多药（MDR-TB）甚至广泛耐药（XDR-TB）菌株的增加，代表了一种未得到满足的医疗需求，需要替代方法。因此，在本项目中，我们将评估一种很有前景的抗结核天然产物化合物类，Callyaerins。Callyaerins是一种具有罕见(Z)-2,3-二氨基丙烯酰胺（DAA）片段的环肽，具有良好的抗结核生长特性和合适的治疗窗口。然而，到目前为止，它们潜在的作用方式仍然未知。通过化学生物学的共同努力，我们将研究这类有前途的化合物的潜在范围和分子机制。为此，我们将通过化学合成和生物实验来提高Callyaerins的抗结核作用和治疗窗口，并推断其潜在的构效关系。此外，我们将利用化学蛋白质组学和化学遗传学结合生化方法，鉴定和功能表征结核分枝杆菌中Callyaerins的直接抗结核靶点和分子机制。最后，我们将在相关的结核病动物模型中对Callyaerins进行评估。因此，我们的项目将有助于应对开发替代性抗结核化疗的挑战，并确定可用于抗击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.