What is the MOA of sulfonamides?

• A. They interfere with folic acid synthesis by preventing addition of PABA into the folic acid molecule through competing with PABA for receptor binding
• B. They inhibit ribosomal protein synthesis
• C. They disrupt cell wall
• D. They intercalate DNA

Answer: (A)

Sulfonamides block bacterial folate synthesis by acting as PABA analogs and competitively inhibiting the enzyme dihydropteroate synthase. This prevents the incorporation of PABA into dihydropteroate, stopping the production of dihydrofolic acid and, downstream, tetrahydrofolate—an essential cofactor for thymidylate and purine synthesis needed for DNA replication. Humans don’t synthesize folate de novo, so they’re less affected, which gives selective toxicity. Often they’re paired with trimethoprim, which blocks the next step (dihydrofolate reductase), creating a more complete blockade of folate pathways and stronger antibacterial effect. Other MOAs, like inhibiting ribosomal protein synthesis, disrupting the cell wall, or intercalating DNA, do not describe how sulfonamides work.