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© Carmen Buchrieser, Marie-Christine Prevost
Legionella pneumophila et son flagelle, bactérie responsable de pneumopathie aigue grave. Bactérie de l'environnement , l'émergence récente de cette maladie s'explique par son affinité pour les systèmes modernes d'alimentation en eau comme les tours de refroidissement. Image colorisée.
Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Chembiochem : a European journal of chemical biology - 10 Sep 2024

Barbachowska M, Harviel T, Nicchi S, Danckaert A, Ghazarian M, Chiaravalli J, Buchrieser C, Rolando M, Arimondo P

Link to Pubmed [PMID] – 39252664

Link to DOI – 10.1002/cbic.202400293

Chembiochem 2024 Sep; (): e202400293

Resistance to anti-microbial agents is a world-wide health threat. Thus there is an urgent need for new treatments. An alternative approach to disarm pathogens consists in developing drugs targeting epigenetic modifiers. Bacterial pathogens can manipulate epigenetic regulatory systems of the host to bypass defences to proliferate and survive. One example is Legionella pneumophila, a Gram-negative intracellular pathogen that targets host chromatin with a specific, secreted bacterial SET-domain methyltransferase named RomA. This histone methyltransferase specifically methylates H3K14 during infection and is responsible for changing the host epigenetic landscape upon L. pneumophila infection. To inhibit RomA activity during infection, we developed a reliable high-content imaging screening assay, which we used to screen an in-house chemical library developed to inhibit DNA and histone methyltransferases. This assay was optimised using monocytic leukemic THP-1 cells differentiated into macrophages infected with L. pneumophila in a 96- or 384-well plate format using the Opera Phenix® (Perkin Elmer) confocal microscope, combined with Columbus™ software for automated image acquisition and analysis. H3K14 methylation was followed in infected, single cells and cytotoxicity was assessed in parallel. A first pilot screening of 477 compounds identified a potential starting point for inhibitors of H3K14 methylation.