| Summary: | Due to increasing mupirocin resistance, alternatives for <i>Staphylococcus aureus</i> nasal decolonization are urgently needed. Adhesion inhibitors are promising new preventive agents that may be less prone to induce resistance, as they do not interfere with the viability of <i>S. aureus</i> and therefore exert less selection pressure. We identified promising adhesion inhibitors by screening a library of 4208 compounds for their capacity to inhibit <i>S. aureus</i> adhesion to A-549 epithelial cells in vitro in a novel automated, imaging-based assay. The assay quantified DAPI-stained nuclei of the host cell; attached bacteria were stained with an anti-teichoic acid antibody. The most promising candidate, aurintricarboxylic acid (ATA), was evaluated in a novel persistent <i>S. aureus</i> nasal colonization model using a mouse-adapted <i>S. aureus</i> strain. Colonized mice were treated intranasally over 7 days with ATA using a wide dose range (0.5–10%). Mupirocin completely eliminated the bacteria from the nose within three days of treatment. In contrast, even high concentrations of ATA failed to eradicate the bacteria. To conclude, our imaging-based assay and the persistent colonization model provide excellent tools to identify and validate new drug candidates against <i>S. aureus</i> nasal colonization. However, our first tested candidate ATA failed to induce <i>S. aureus</i> decolonization.
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