Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis.

Abstract

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 on the basis of target-based drug discovery. Fifty years later, PAS continues to be used to treat tuberculosis. PAS is assumed to inhibit dihydropteroate synthase (DHPS) in Mycobacterium tuberculosis by mimicking the substrate p-aminobenzoate (PABA). However, we found that sulfonamide inhibitors of DHPS inhibited growth of M. tuberculosis only weakly because of their intracellular metabolism. In contrast, PAS 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.

DOI: 10.1126/science.1228980

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@article{Chakraborty2013ParaaminosalicylicAA, title={Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis.}, author={Sumit Chakraborty and Todd D Gruber and Clifton Earl Barry and Helena I. M. Boshoff and Kyu Y. Rhee}, journal={Science}, year={2013}, volume={339 6115}, pages={88-91} }