西亚试剂：Para-Aminosalicylic Acid Acts as an Alternative Substrate o

Para-Aminosalicylic Acid Acts as an Alternative Substrate of Folate Metabolism in Mycobacterium tuberculosis

Sumit Chakraborty1,2, Todd Gruber3, Clifton E. Barry III3, Helena I. Boshoff3, Kyu Y. Rhee1,2,*

Folate biosynthesis is an established anti-infective target, and the antifolate para-aminosalicylic acid (PAS) was one of the first anti-infectives introduced into clinical practice based on target-based drug discovery. Fifty years later, PAS continues in use for tuberculosis. PAS is assumed to inhibit dihydropteroate synthase (DHPS) in Mycobacterium tuberculosis (M. tuberculosis) by mimicking the substrate, p-aminobenzoate (PABA). However, we found that sulfonamide inhibitors of DHPS inhibited growth of M. tuberculosis only weakly due to their intracellular metabolism. PAS, by contrast, served as a replacement substrate for DHPS. Products of PAS metabolism at this and subsequent steps in folate metabolism inhibited those enzymes, competing with their substrates. PAS is thus a prodrug that blocks growth of M. tuberculosis when its active forms are generated by enzymes in the pathway they poison.

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