Either alone or in combination with trimethoprim, sulfonamides are used to treat a variety of bacterial diseases such as UTIs caused by E. coli, otitis media caused by S. pneumoniae or H. influenzae in children, shigellosis, nocardiosis, and chancroid. In combination, they are also the drugs of choice for two additional diseases, toxoplasmosis and Pneumocystis pneumonia. The sulfonamides are a large family of bacteriostatic drugs that are produced by chemical synthesis. In 1935, the parent compound, sulfanilamide, became the first clinically effective antimicrobial agent.
The mode of action of sulfonamides is to block the syn thesis of tetrahydrofolic acid, which is required as a methyl donor in the synthesis of the nucleic acid precursors adenine, guanine, and thymine. Sulfonamides are structural analogues of p-aminobenzoic acid (PABA). PABA condenses with a pteridine compound to form dihydropteroic acid, a precursor of tetrahydrofolic acid (Figure 1). Sulfonamides compete with PABA for the active site of the enzyme dihydropteroate synthetase.
Fig1. Mechanism of action of sulfonamides and trimethoprim. A: Comparison of the structures of p-aminobenzoic acid (PABA) and sulfanilamide. Note that the only difference is that PABA has a carboxyl (COOH) group, whereas sulfanilamide has sulfonamide (SO2NH2) group. B: Structure of trimethoprim. C: Inhibition of the folic acid pathway by sulfonamide and trimethoprim. Sulfonamides inhibit the synthesis of dihydrofolic acid (DHF) from its precursor PABA. Trimethoprim inhibits the synthesis of tetrahydrofolic acid (THF) from its precursor DHF. Loss of THF inhibits DNA synthesis because THF is required to transfer a methyl group onto uracil to produce thymidine, an essential component of DNA.
The basis of the selective action of sulfonamides on bacteria is that many bacteria synthesize their folic acid from PABA containing precursors, whereas human cells require preformed folic acid as an exogenous nutrient because they lack the enzymes to synthesize it. Human cells, therefore, bypass the step at which sulfonamides act. Bacteria that can use preformed folic acid are similarly resistant to sulfonamides.
The p-amino group on the sulfonamide is essential for its activity. Modifications are therefore made on the sulfonic acid side chain. Sulfonamides are inexpensive and infrequently cause side effects. However, drug-related fever, rashes, photosensitivity (rash upon exposure to sunlight), and bone marrow suppression can occur. They are the most common group of drugs that cause erythema multiforme and its more severe forms, Stevens Johnson syndrome and toxic epidermal necrolysis.
