Sortase A-Inhibitory Coumarins from the Folk Medicinal Plant <i>Poncirus trifoliata</i>

Abstract

Thirteen coumarins (<b>1</b>-<b>13</b>), including five new compounds (<b>1</b>-<b>5</b>), were isolated from the folk medicinal plant <i>Poncirus trifoliata</i>. Combined spectroscopic analyses revealed that coumarins <b>1</b>-<b>4</b> are bis-isoprenylated coumarins with diverse oxidation patterns, while <b>5</b> is an enantiomeric di-isoprenylated coumarin. The absolute configurations of the stereogenic centers in the isoprenyl chains were assigned through MTPA and MPA methods, and those of the known compounds triphasiol (<b>6</b>) and ponciol (<b>7</b>) were also assigned using similar methods. These coumarins inhibited significantly <i>Staphylococcus aureus</i>-derived sortase A (SrtA), a transpeptidase responsible for anchoring surface proteins to the peptidoglycan cell wall in Gram-positive bacteria. The present results obtained indicated that the bioactivity and underlying mechanism of action of these coumarins are associated with the inhibition of SrtA-mediated <i>S. aureus</i> adhesion to eukaryotic cell matrix proteins including fibrinogen and fibronectin, thus potentially serving as SrtA inhibitors.