Abstract
Due to increasing mupirocin resistance, alternatives for Staphylococcus aureus 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 S. aureus and therefore exert less selection pressure. We identified promising adhesion inhibitors by screening a library of 4208 compounds for their capacity to inhibit S. aureus 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 S. aureus nasal colonization model using a mouse-adapted S. aureus 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 S. aureus nasal colonization. However, our first tested candidate ATA failed to induce S. aureus decolonization.
Highlights
Nasal colonization with Staphylococcus aureus is a major risk factor for invasive staphylococcal infections [1,2]
Our first aim was the development of an automated microscopy-based method that allows the screening of several thousand substances for compounds that inhibit the adhesion of S. aureus to human lung epithelial cells (A-549) [17,32,33,34]
An incubation time of one hour at room temperature (RT) was found most suitable, since longer incubation times or higher temperatures led to a bias due to bacterial proliferation and/or compounds that have an influence on bacterial growth rather than on adhesion
Summary
Nasal colonization with Staphylococcus aureus is a major risk factor for invasive staphylococcal infections [1,2]. To prevent endogenous infection as well as transmission within the hospital, newly admitted patients are routinely screened for MRSA colonization and decolonized using the antibiotic mupirocin [4]. Increasing bacterial resistance to mupirocin with a prevalence exceeding 13% for MRSA [5] and restrictions for its use have created a need for alternatives [6,7]. S. aureus nasal carriage have been explored, including antibiotics, such as neomycin [8], polysporin [9], and bacitracin [10], bacteriocins such as lysostaphin [11], as well as fatty acid derivatives (lauric acid monoesters) [12], and cationic synthetic polymers [13].
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