| Autor: |
Ouertatani-Sakouhi H; Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland., Kicka S; Department of Biochemistry, University of Geneva, Geneva, Switzerland., Chiriano G; Pharmaceutical biochemistry, School of pharmaceutical sciences, University of Geneva, University of Lausanne, 30 Quai Ernst Ansermet, Geneva, Switzerland., Harrison CF; Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich, Munich, Germany., Hilbi H; Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich, Munich, Germany.; Institute of Medical Microbiology, Department of Medicine, University of Zürich, Gloriastrasse 30/32, Zürich, Switzerland., Scapozza L; Pharmaceutical biochemistry, School of pharmaceutical sciences, University of Geneva, University of Lausanne, 30 Quai Ernst Ansermet, Geneva, Switzerland., Soldati T; Department of Biochemistry, University of Geneva, Geneva, Switzerland., Cosson P; Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. |
| Abstrakt: |
Tuberculosis remains one of the major threats to public health worldwide. Given the prevalence of multi drug resistance (MDR) in Mycobacterium tuberculosis strains, there is a strong need to develop new anti-mycobacterial drugs with modes of action distinct from classical antibiotics. Inhibitors of mycobacterial virulence might target new molecular processes and may represent a potential new therapeutic alternative. In this study, we used a Dictyostelium discoideum host model to assess virulence of Mycobacterium marinum and to identify compounds inhibiting mycobacterial virulence. Among 9995 chemical compounds, we selected 12 inhibitors of mycobacterial virulence that do not inhibit mycobacterial growth in synthetic medium. Further analyses revealed that 8 of them perturbed functions requiring an intact mycobacterial cell wall such as sliding motility, bacterial aggregation or cell wall permeability. Chemical analogs of two compounds were analyzed. Chemical modifications altered concomitantly their effect on sliding motility and on mycobacterial virulence, suggesting that the alteration of the mycobacterial cell wall caused the loss of virulence. We characterized further one of the selected compounds and found that it inhibited the ability of mycobacteria to replicate in infected cells. Together these results identify new antimycobacterial compounds that represent new tools to unravel the molecular mechanisms controlling mycobacterial pathogenicity. The isolation of compounds with anti-virulence activity is the first step towards developing new antibacterial treatments. |
