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To understand the mechanism of action of this class of drugs, we need to first review the synthesis of folic acid (Figure 30–1). Bacteria cannot absorb folic acid but must make it from PABA (para-aminobenzoic acid), pteridine, and glutamate. For humans, folic acid is a vitamin. We cannot synthesize it. This makes this metabolic pathway a nice, selective target for antimicrobial agents.
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Sulfonamides and trimethoprim inhibit synthesis of folate at two different sites.
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The sulfonamides are structurally similar to PABA and block the incorporation of PABA into dihydropteroic acid. Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. This enzyme is present in humans, but trimethoprim has a lower affinity for the human enzyme. There are other examples of folate reductase inhibitors that we will consider later (pyrimethamine and methotrexate).
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The combination of sulfonamides and trimethoprim is synergistic, and they are rarely used alone. Sulfamethoxazole is the sulfonamide used in combination with trimethoprim because sulfonamides and trimethoprim have matching half-lives.
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There are other sulfonamides; please check your textbook. Note that sulfasalazine is also used to treat inflammatory bowel disease (see Chapter 44).
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These folate antagonists are broad-spectrum agents that are effective against gram-positive and gram-negative organisms.
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The combination of sulfamethoxazole and trimethoprim, called cotrimoxazole, is probably the most commonly used drug in this group. It is used for urinary tract infections and Pneumocystis carinii pneumonitis, among other things. These drugs are orally absorbed.