Bacteria need folic acid to synthesize the nucleic acids that make up their DNA. Sulfonamides inhibit folate synthesis by targeting dihydropteroate synthase (DHPS) in the folic acid pathway. As structural analogs to 4-aminobenzoic acid (PABA), they competitively inhibit the incorporation of PABA into folic acid (Figure 1). Since eukaryotic cells are not dependent on endogenous synthesis of folic acid and generally lack DHPS, these cells are not targeted. Resistant mutants encode variants of DHPS that are insensitive to sulfonamides. To overcome this, sulfonamides are now commonly used in combination with trimethoprim, an inhibitor of dihydrofolate reductase (DHFR) that reduces dihydrofolic acid to tetrahydrofolic acid to decrease folic acid synthesis.
Figure 1: Antibiotics that are structural analogs of PABA interfere with folic acid synthesis and work synergistically with DHFR inhibitors.