Callyaerins as lead structures and chemical probes for antitubercular drug discovery
Final Report Abstract
Spread of antimicrobial resistances in the pathogen Mycobacterium tuberculosis remains a public health challenge. Thus, there is a continuous need for new therapeutic options with modes-of-action differing from current antibiotics. Previously, bioactivity-guided isolation identified the callyaerins, a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-diaminoacrylamide unit, as promising antitubercular agents. In this project, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of the structural determinants relevant for their antibacterial activity. The antitubercular callyaerins are bacteriostatics selectively active against M. tuberculosis, including extensively drug-resistant (XDR) strains, with minimal cytotoxicity against human cells and a promising intracellular activity in a macrophage infection model. Via spontaneous resistance mutant screens and various chemical proteomics approaches, we showed that they act by direct targeting of the non-essential, M. tuberculosisspecific putative membrane protein Rv2113, thereby triggering a complex stress response in M. tuberculosis characterized by global downregulation of lipid biosynthesis, cell division, DNA repair and replication. Our study thus not only identifies Rv2113 as a new M. tuberculosisspecific target for antitubercular drugs, which should result in less harm of the microbiome and weaker resistance development in off-target pathogens. It furthermore demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.
Publications
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Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival. Cell, 186(10), 2176-2192.e22.
Hoi, David M.; Junker, Sabryna; Junk, Lukas; Schwechel, Kristin; Fischel, Katharina; Podlesainski, David; Hawkins, Paige M.E.; van Geelen, Lasse; Kaschani, Farnusch; Leodolter, Julia; Morreale, Francesca Ester; Kleine, Stefan; Guha, Somraj; Rumpel, Klaus; Schmiedel, Volker M.; Weinstabl, Harald; Meinhart, Anton; Payne, Richard J.; Kaiser, Markus ... & Clausen, Tim
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The anti-tubercular callyaerins target theMycobacterium tuberculosis-specific non-essential membrane protein Rv2113. Cold Spring Harbor Laboratory.
Podlesainski, David; Adeniyi, Emmanuel T.; Gröner, Yvonne; Schulz, Florian; Krisilia, Violetta; Rehberg, Nidja; Richter, Tim; Sehr, Daria; Xie, Huzhuyue; Simons, Viktor E.; Kiffe-Delf, Anna-Lene; Kaschani, Farnusch; Ioerger, Thomas R.; Kaiser, Markus & Kalscheuer, Rainer
