Biol. Pharm. Bull. 29(8) 1751—1755 (2006)

molecules with important functions, such as adherence, invasion, signaling, and interaction with the host immune system or the environment. In Gram-positive bacteria, many surface proteins are anchored to the cell wall envelope by an enzyme called sortase, which recognizes a conserved carboxylic sorting motif. Two sortase isoforms, sortase A (SrtA) and sortase B (SrtB), have been identified in Staphylococcus aureus. While the SrtB isoform appears to be important in heme iron acquisition and iron homeostasis, numerous genetic knockout experiments have shown that the SrtA isoform plays a critical role in the pathogenesis of Gram-positive bacteria by modulating the ability of the bacterium to adhere to host tissue via the covalent anchoring of adhesions and other virulence-associated proteins to cell wall peptidoglycan. SrtA is constitutively expressed and cleaves the amide bond between the threonine and glycine of the LPXTG motif. Conversely, SrtB recognizes the surface protein substrate bearing the NPQTN motif sorting signal. S. aureus mutants lacking SrtA fail to display surface proteins and are defective in the establishment of infections without affecting microbial viability. Therefore inhibitors of SrtA might consequently be promising candidates for the treatment and/or prevention of Gram-positive bacterial infections. There have only been a few reports in the literature describing inhibitors of sortase, due in part to the fact that importance of sortase as a new target has only recently been acknowledged. Flavonoids represent a large group of plant phenols. These compounds can be classified into flavones, flavonols, flavanones, isoflavones, and anthocyanidins. More than 4000 flavonoid compounds have been found. These compounds have many biological and pharmacologic activities including antitumor, antiinflammatory, and antioxidative effects. Flavonols, the subgroup of flavonoids represented mainly by quercetin and kaempferol, are abundant in fruits and vegetables. During the course of our search for SrtA inhibitors from medicinal plants, we found that the EtOAc extract from Rhus verniciflua (bark) exhibited strong SrtA-inhibitory activity. Bioassay-guided separation of the extract using various chromatographic techniques yielded an active compound. Based on the results of combined spectral analyses and comparison of spectral data with those of known compounds, the active compound was identified as quercetin, because its NMR and EI-MS spectra were in good agreement with those reported previously. Therefore understanding the structural basis of sortase inhibition by flavonols would provide important clues for the drug design of sortase inhibitors. In this study, we investigated whether natural flavonols inhibit the activity of S. aureus sortases and the sortase-mediated S. aureus binding to cell-matrix protein fibrinogen.