title: 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.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Todd
authors.initials: T
authors.lastname: Gruber
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Kyu Y
authors.initials: KY
authors.lastname: Rhee
mesh_terms: D010131:Aminosalicylic Acid / Q000378:metabolism* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000378:metabolism* / Q000494:pharmacology; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism*; D018716:Molecular Mimicry; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D000995:Antitubercular Agents; D011355:Prodrugs; D010131:Aminosalicylic Acid; D005492:Folic Acid; D004094:Dihydropteroate Synthase