Discovery of <i>Staphylococcus aureus</i> Adhesion Inhibitors by Automated Imaging and Their Characterization in a Mouse Model of Persistent Nasal Colonization

• Main Authors: Liliane Maria Fernandes de Oliveira, Marina Steindorff, Murthy N. Darisipudi, Daniel M. Mrochen, Patricia Trübe, Barbara M. Bröker, Mark Brönstrup, Werner Tegge, Silva Holtfreter
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: Microorganisms
• Subjects: <i>Staphylococcus aureus</i>; colonization; mouse; JSNZ; aurintricarboxylic acid; ATA
• Online Access: https://www.mdpi.com/2076-2607/9/3/631

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.