1. The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113.
- Author
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Podlesainski D, Adeniyi ET, Gröner Y, Schulz F, Krisilia V, Rehberg N, Richter T, Sehr D, Xie H, Simons VE, Kiffe-Delf AL, Kaschani F, Ioerger TR, Kaiser M, and Kalscheuer R
- Subjects
- Humans, Structure-Activity Relationship, Membrane Proteins metabolism, Membrane Proteins genetics, Membrane Proteins antagonists & inhibitors, Peptides, Cyclic pharmacology, Peptides, Cyclic chemistry, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis metabolism, Microbial Sensitivity Tests, Bacterial Proteins metabolism, Bacterial Proteins genetics, Bacterial Proteins antagonists & inhibitors, Antitubercular Agents pharmacology, Antitubercular Agents chemistry
- Abstract
Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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