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

• DOI: 10.1101/2023.07.12.548660
• Publication Date: 2023-07-13T03:45:13Z
• Authors: David Podlesainski; Emmanuel T. Adeniyi; Yvonne Gröner; Florian Schulz; Violetta Krisilia; Nidja Rehberg; Tim Richter; Daria Sehr; Huzhuyue Xie; Viktor E. Simons; Anna-Lene Kiffe-Delf; Farnusch Kaschani; Thomas R. Ioerger; Markus Kaiser; Rainer Kalscheuer
• Keywords: Antimycobacterial

ABSTRACT Spread of antimicrobial resistances in the pathogen Mycobacterium tuberculosis remains a public health challenge. Thus, there is continuous need for new therapeutic options with modes-of-action differing from current antibiotics. Previously, bioactivity-guided isolation identified callyaerins, class hydrophobic cyclopeptides an unusual ( Z )-2,3-di-aminoacrylamide unit, as promising antitubercular agents. In this study, we investigated molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled identification structural determinants relevant antibacterial activity. The callyaerins are bacteriostatics selectively active against M. , including extensively drug-resistant (XDR) strains, minimal cytotoxicity human cells and intracellular activity macrophage infection model. Via spontaneous resistance mutant screens various chemical proteomics approaches, showed that they act by direct targeting non-essential, -specific putative membrane protein Rv2113, thereby triggering complex stress response characterized global downregulation lipid biosynthesis, cell division, DNA repair replication. Our study thus not only identifies Rv2113 target drugs, which should result less harm microbiome weaker development off-target pathogens. It furthermore demonstrates also non-essential proteins may represent efficacious targets drugs.