Microbiology, 2021

14.3 • Mechanisms of Antibacterial Drugs 577
folic acid synthesis (Figure 14.12). By inhibiting the enzyme involved in the production of dihydrofolic acid,
sulfonamides block bacterial biosynthesis of folic acid and, subsequently, pyrimidines and purines required
for nucleic acid synthesis. This mechanism of action provides bacteriostatic inhibition of growth against a
wide spectrum of gram-positive and gram-negative pathogens. Because humans obtain folic acid from food
instead of synthesizing it intracellularly, sulfonamides are selectively toxic for bacteria. However, allergic
reactions to sulfa drugs are common. The sulfones are structurally similar to sulfonamides but are not
commonly used today except for the treatment of Hansen’s disease (leprosy).
Trimethoprim is a synthetic antimicrobial compound that serves as an antimetabolite within the same folic
acid synthesis pathway as sulfonamides. However, trimethoprim is a structural analogue of dihydrofolic acid
and inhibits a later step in the metabolic pathway (Figure 14.12). Trimethoprim is used in combination with
the sulfa drug sulfamethoxazole to treat urinary tract infections, ear infections, and bronchitis. As discussed,
the combination of trimethoprim and sulfamethoxazole is an example of antibacterial synergy. When used
alone, each antimetabolite only decreases production of folic acid to a level where bacteriostatic inhibition of
growth occurs. However, when used in combination, inhibition of both steps in the metabolic pathway
decreases folic acid synthesis to a level that is lethal to the bacterial cell. Because of the importance of folic
acid during fetal development, sulfa drugs and trimethoprim use should be carefully considered during early
pregnancy.
The drug isoniazid is an antimetabolite with specific toxicity for mycobacteria and has long been used in
combination with rifampin or streptomycin in the treatment of tuberculosis. It is administered as a prodrug,
requiring activation through the action of an intracellular bacterial peroxidase enzyme, forming isoniazidnicotinamide
adenine dinucleotide (NAD) and isoniazid-nicotinamide adenine dinucleotide phosphate
(NADP), ultimately preventing the synthesis of mycolic acid, which is essential for mycobacterial cell walls.
Possible side effects of isoniazid use include hepatotoxicity, neurotoxicity, and hematologic toxicity (anemia).