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bioRxiv · 10.1101/2023.07.12.548660

The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113

Podlesainski, D.·Adeniyi, E. T.·Groener, Y.·Schulz, F.·Krisilia, V.·Rehberg, N.·Richter, T.·Sehr, D.·Xie, H.·Simons, V. E.·Kiffe-Delf, A.-L.·Kaschani, F.·Ioerger, T. R.·Kaiser, M.·Kalscheuer, R.
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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-di-aminoacrylamide unit, as promising antitubercular agents. In this study, 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. tuberculosis-specific 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. tuberculosis-specific 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.

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Podlesainski, D., Adeniyi, E. T., Groener, Y., Schulz, F., Krisilia, V., Rehberg, N., Richter, T., Sehr, D., Xie, H., Simons, V. E., Kiffe-Delf, A.-L., Kaschani, F., Ioerger, T. R., Kaiser, M., Kalscheuer, R.. 2023-07-12. The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113. https://doi.org/10.1101/2023.07.12.548660

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