The anti-tubercular callyaerins target the Mycobacterium tuberculosis -specific non-essential membrane protein Rv2113
The anti-tubercular callyaerins target the Mycobacterium tuberculosis -specific non-essential membrane protein Rv2113
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.
Podlesainski David、Schulz Florian、Rehberg Nidja、Kiffe-Delf Anna-Lene、Ioerger Thomas R.、Kaiser Markus、Kalscheuer Rainer、Adeniyi Emmanuel T.、Simons Viktor E.、Krisilia Violetta、Kaschani Farnusch、Xie Huzhuyue、Richter Tim、Gr?ner Yvonne、Sehr Daria
Center of Medical Biotechnology, Chemical Biology, University Duisburg-EssenCenter of Medical Biotechnology, Chemical Biology, University Duisburg-EssenInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine UniversityInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine UniversityDepartment of Computer Science, Texas A&M University, College StationCenter of Medical Biotechnology, Chemical Biology, University Duisburg-EssenInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine UniversityInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine UniversityInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine UniversityInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine UniversityCenter of Medical Biotechnology, Chemical Biology, University Duisburg-EssenCenter of Medical Biotechnology, Chemical Biology, University Duisburg-EssenCenter of Medical Biotechnology, Chemical Biology, University Duisburg-EssenInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine UniversityCenter of Medical Biotechnology, Chemical Biology, University Duisburg-Essen
微生物学药学分子生物学
Podlesainski David,Schulz Florian,Rehberg Nidja,Kiffe-Delf Anna-Lene,Ioerger Thomas R.,Kaiser Markus,Kalscheuer Rainer,Adeniyi Emmanuel T.,Simons Viktor E.,Krisilia Violetta,Kaschani Farnusch,Xie Huzhuyue,Richter Tim,Gr?ner Yvonne,Sehr Daria.The anti-tubercular callyaerins target the Mycobacterium tuberculosis -specific non-essential membrane protein Rv2113[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2023.07.12.548660.点此复制
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