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Tetrahydrofolate

Multiple enzymes and reactions

Thymine, guanine, and adenine nucleotides

Figure 21.8 Inhibitors of the Folate Pathway (a) The chemical structure of PABA and a sulfa drug (sulfanilamide). (b) The sulfonamides and trimethoprim interfere with different steps of the pathway that leads initially to the synthesis of folic acid and ultimately to the synthesis of a coenzyme required for nucleotide biosynthesis.

The Sulfonamides

Sulfonamides and related compounds, collectively referred to as sulfa drugs, inhibit the growth of many Gram-positive and Gram-negative bacteria. They are structurally similar to para-aminobenzoic acid (PABA), a substrate in the pathway for folic acid biosynthesis. Because of this similarity, the enzyme that normally binds PABA preferentially binds sulfa drugs, resulting in its competitive inhibition. Human cells lack this enzyme, providing the basis for the selective toxicity of the sulfonamides. Resistance of bacteria to the sulfonamides is most often due to the acquisition of a plasmid-encoded enzyme that has a lower affinity for the drug. ■ competitive inhibition, p. 141

Trimethoprim

Trimethoprim inhibits the bacterial enzyme that catalyzes a metabolic step following the one inhibited by sulfonamides. Fortunately, the drug has little effect on the analogous enzyme in human cells. The combination of trimethoprim and a sulfonamide has a syner-gistic effect, and they are often used together to treat urinary tract infections. The most common mechanism of resistance is a plasmid-encoded alternative enzyme that has a lower affinity for the drug. Unfortunately, the genes encoding resistance to trimethoprim and sulfonamide are often carried on the same plasmid.

Antibacterial Medications that Interfere with Cell Membrane Integrity

A few antimicrobial drugs damage bacterial membranes. Polymyxin B, a common ingredient in first-aid skin ointments, binds to the membrane of Gram-negative cells and alters their permeability, leading to leakage of cellular contents and eventual death of the cells. Unfortunately, these drugs also bind to eukaryotic

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