10.5061/DRYAD.VH36N
Chakraborty, Sumit
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Gruber, Todd
National Institutes of Health
Barry III, Clifton E.
National Institutes of Health
Boshoff, Helena I.
National Institutes of Health
Rhee, Kyu Y.
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Data from: Para-aminosalicylic acid acts as an alternative substrate of
folate metabolism in Mycobacterium tuberculosis
Dryad
dataset
2013
Mycobacterium tuberculosis
2013-03-01T18:32:33Z
2013-03-01T18:32:33Z
en
https://doi.org/10.1126/science.1228980
279546 bytes
1
CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
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.
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