Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis Academic Article uri icon

Overview

MeSH Major

  • Aminosalicylic Acid
  • Antitubercular Agents
  • Dihydropteroate Synthase
  • Folic Acid
  • Mycobacterium tuberculosis
  • Prodrugs

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.

publication date

  • January 4, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3792487

Digital Object Identifier (DOI)

  • 10.1126/science.1228980

PubMed ID

  • 23118010

Additional Document Info

start page

  • 88

end page

  • 91

volume

  • 339

number

  • 6115