Callyaerins as lead structures and chemical probes for antitubercular drug discovery

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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.