The antibiotic trimethoprim, used primarily for the treatment of urinary tract infections, works by an unexpected ‘domino effect’ in which two enzymes in a pathway are both inhibited by a single drug, according to a paper online this week in Nature Chemical Biology. The work reveals new insights into the mechanism of a clinically used drug and highlights the potential of looking at metabolic pathways to understand drug action.
Trimethoprim is known to inhibit a bacterial enzyme called dihydrofolate reductase (DHFR). By using a method for simultaneously measuring all of the folate-related chemicals in a bacterial cell, Joshua Rabinowitz and colleagues found that trimethoprim was blocking not just the activity of DHFR, but also another enzyme in folate metabolism. The second enzyme was not directly inhibited by trimethoprim. Instead, inhibiting DHFR caused accumulation of the substrate, dihydrofolate, which was an inhibitor of the second enzyme. Therefore, trimethoprim created a cascade of enzyme inhibition.