Wikimedia, NIAIDDrugs that interfere with the synthesis of the
essential nutrient folate are among the oldest antibiotics
around. Now, after decades of successful use, researchers are
using metabolomics to discover how, exactly, they work. One such
drug, commonly used to treat tuberculosis (TB), is processed by
a key enzyme in folate biosynthesis, breaking down into
different products that interfere with enzymes that act later in
the pathway. The results, published today (November 1) in
Science, contradict the previous belief that the drug, para-
aminosalicylic acid (PAS), worked by simply binding the enzyme
such that it was not available to process a folate precursor,
and may point to novel TB drug targets and antimicrobial
strategies beyond enzyme inhibition. “It’s a really good example
of how we don’t really understand how many drugs work,” said
Eric Rubin, a tuberculosis researcher at Harvard University who
did not participate in the research. “We often operate under the
simple assumption that drugs inhibi