Nonsteroidal Anti-Inflammatory Drugs and Other Anthranilic Acids Inhibit the Na+/Dicarboxylate Symporter from Staphylococcus aureus

The Na+/dicarboxylate symporterfrom Staphylococcus aureus, named SdcS, is a member of the divalent anion sodium symporter(DASS) family that also includes the mammalian SLC13 Na+/dicarboxylate cotransporters, NaDC1 and NaCT. The mammalian members of the family are sensitive to inhibition by anthranilic acidderivatives such as N-(p-amylcinnamoyl) anthranilic acid(ACA), which act as slow inhibitors. This study shows that SdcS is inhibited by ACA as well as the fenamate nonsteroidalanti-inflammatory drugs, flufenamate and niflumate. The inhibition was rapid and reversible. The IC50 for ACA was approximately 55 μM. Succinatekinetics by SdcS were sigmoidal, with a K0.5 of 9 μM and a Hill coefficient of 1.5. Addition of ACA decreased the Vmax and increased the Hill coefficient without affecting the K0.5, consistent with its activity as a negative modulator of SdcS activity. ACA inhibition was not correlated with the K0.5 for succinatein SdcS mutants, and ACA did not affect the reactivity of the N108C mutan...