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Front Microbiol,
2019]
Antimicrobial drug discovery against drug-resistant bacteria is an urgent need. Beyond agents with direct antibacterial activity, anti-virulent molecules may also be viable compounds to defend against bacterial pathogenesis. Using a high throughput screen (HTS) that utilized <i>Caenorhabditis elegans</i> infected with methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) strain of MW2, we identified 4-(1,3-dimethyl-2,3-dihydro-1H-benzimidazol-2-yl)phenol (BIP). Interestingly, BIP had no <i>in vitro</i> inhibition activity against MW2, at least up to 64 g/ml. The lack of direct antimicrobial activity suggests that BIP could inhibit bacterial virulence factors. To explore the possible anti-virulence effect of the identified molecule, we first performed real-time PCR to examine changes in virulence expression. BIP was highly active against MRSA virulence factors at sub-lethal concentrations and down-regulated virulence regulator genes, such as <i>agrA</i> and <i>codY</i>. However, the benzimidazole derivatives omeprazole and pantoprazole did not down-regulate virulence genes significantly, compared to BIP. Moreover, the BIP-pretreated MW2 cells were more vulnerable to macrophage-mediated killing, as confirmed by intracellular killing and live/dead staining assays, and less efficient in establishing a lethal infection in the invertebrate host <i>Galleria mellonella</i> (<i>p</i> = 0.0131). We tested the cytotoxicity of BIP against human red blood cells (RBCs), and it did not cause hemolysis at the highest concentration tested (64 g/ml). Taken together, our findings outline the potential anti-virulence activity of BIP that was identified through a <i>C. elegans</i>-based, whole animal based, screen.