ing used in medicine, the sulfonamide moiety is found in diuretics (furosemide, thiazide, and thi-azide-like, carbonic anhyclrase inhibitors) and oral hypoglycemics (chlorpropamide, glyburide, glipizide, glimepiride, and other sulfonylureas).
The sulfonamides are selective for a key reaction found only in bacteria. Most bacteria synthesize their own folic acid. In contrast, humans obtain their folic acid from food and vitamin supplements. Therefore, in bacteria sulfonamides block folic acid biosynthesis by competitive inhibition of dihydropteroate synthase, which is the enzyme used by bacteria to incorporatep-aminobenzoic acid to form dihy-dropteroic acid (Fig. 7.7). Upon the addition of glutamic acid to the latter, the bacteria synthesize dihydrofolic acid (FAH2, FH2, DHF). A second antibiotic, trimethoprim (23), selectively inhibits bacterial dihydrofolate reduc-
Selective Toxicity tase. As long as the patient's folic acid status is adequate, there is minimal metabolic toxicity from the sulfonamides or trimethoprim.
In contrast with these two antibacterial antibiotics, methotrexate (24) is one of the most used cytotoxic drugs for malignancies and, in lower doses, an immunosuppresive in autoimmune diseases (i.e., psoriasis and rheumatoid arthritis). Methotrexate inhibits mammalian dihydrofolate reductase (DHFR), which is found in every cell that uses one of the coen-zyme forms of folic acid. Because of its poor comparative biochemical selectivity, it is common to administer one of the tetrahydrofo-lates as an antidote for methotrexate toxicity.
Dihydrofolate reductase also is a potential site for antifungal antibiotics. The problem was to find a drug that is selective for the fungal version of this enzyme. The result was pyrimethamine (25), which shows a preference for plasmodia dihydrofolate reductase relative to the mammalian enzyme.
2.3.3 Examples Based on the Target Organism. When the pathogen's biochemistry and cell structure becomes more mammalian-like, it becomes more difficult to target a specific site that is significantly different from that found in the host. In some cases, the pathogen
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