Para-aminosalicylic acid is a prodrug targeting dihydrofolate reductase in mycobacterium tuberculosis

Abstract

Background: PAS is an antimycobacterial whose mechanism(s) of action remains elusive. Results: PAS is incorporated into the folate pathway by DHPS-DHFS, generating an anti-metabolite. DHFS and RibD are associated with PAS resistance. Conclusion: Hydroxyl dihydrofolate inhibits DHFR. folC and ribD are drug target genes for identification of clinical PAS resistance. Significance: Metabolite analog incorporation into essential biosynthetic pathways is promising for developing antibacterials. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.