The sulfonamide drugs were the first effective chemotherapeutic agents to be employed systemically for the prevention and cure of bacterial infections in humans. The advent of penicillin and other antibiotics diminished the usefulness of the sulfonamides, but the introduction of the combination of trimethoprim and sulfamethoxazole has increased the use of sulfonamides for the prophylaxis and treatment of specific microbial infections. Sulfonamides are derivatives of para-aminobenzenesulfonamide (sulfanilamide; Figure 52-1) and are congeners of para-aminobenzoic acid. Most of them are relatively insoluble in water, but their sodium salts are readily soluble.
Sulfanilamide and para-aminobenzoic acid. Sulfonamides are derivatives of sulfanilamide and act by virtue of being congeners of para-aminobenzoate (PABA). The antimicrobial and dermatological anti-inflammatory agent dapsone (4,4′-diaminodiphenyl sulfone; see Figure 56-5 and Chapter 65) also bears a resemblance to PABA and sulfanilamide.
The minimal structural prerequisites for antibacterial action are all embodied in sulfanilamide itself. The sulfur must be linked directly to the benzene ring. The para-NH2 group (the N of which has been designated as N4) is essential and can be replaced only by moieties that can be converted in vivo to a free amino group. Substitutions made in the amide NH2 group (position N1) have variable effects on antibacterial activity of the molecule; substitution of heterocyclic aromatic nuclei at N1 yields highly potent compounds.
MECHANISM OF ACTION. Sulfonamides are competitive inhibitors of dihydropteroate synthase, the bacterial enzyme responsible for the incorporation of para-aminobenzoic acid (PABA) into dihydropteroic acid, the immediate precursor of folic acid (Figure 52-2). Sensitive microorganisms are those that must synthesize their own folic acid; bacteria that can use preformed folate are not affected. Toxicity is selective for bacteria because mammalian cells require preformed folic acid, cannot synthesize it, and are thus insensitive to drugs acting by this mechanism.
Steps in folate metabolism blocked by sulfonamides and trimethoprim. Coadministration of a sulfonamide and trimethoprim introduces sequential blocks in the biosynthetic pathway for tetrahydrofolate; the combination is much more effective than either agent alone.
SYNERGISTS OF SULFONAMIDES. Trimethoprim exerts a synergistic effect with sulfonamides. It is a potent and selective competitive inhibitor of microbial dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolate, which is required for 1-carbon transfer reactions. Coadministration of a sulfonamide and trimethoprim introduces sequential blocks in the biosynthetic pathway for tetrahydrofolate (see Figure 52-2); the combination is much more effective than either agent alone.
Sulfonamides have a wide range of antimicrobial activity against both gram-positive and gram-negative bacteria. Resistant strains have become common and the usefulness of these agents has diminished correspondingly. Sulfonamides are bacteriostatic; cellular and humoral defense ...