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

• DOI: 10.1126/science.1228980
• Publication Date: 2012-11-02T06:51:03Z
• Authors: Sumit Chakraborty; Todd Gruber; Clifton E. Barry; Helena I. Boshoff; Kyu Y. Rhee
• Keywords: DHPS; Dihydropteroate synthase

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