Examples of drugs acting by inhibition of nucleic acid syn thesis are the quinolones, pyrimethamine, rifampin, sulfonamides, trimethoprim, and trimetrexate. Rifampin inhibits bacterial growth by binding strongly to the DNA-dependent RNA polymerase of bacteria. Thus, it inhibits bacterial RNA synthesis. Rifampin resistance results from a change in RNA polymerase because of a chromosomal mutation that occurs with high frequency.

All quinolones and fluoroquinolones inhibit microbial DNA synthesis by blocking DNA gyrases, topoisomerase enzymes that play key roles in DNA replication and repair.

For many microorganisms, p-aminobenzoic acid (PABA) is an essential metabolite. The specific mode of action of PABA involves an adenosine triphosphate (ATP)-dependent condensation of a pteridine with PABA to yield dihydropteroic acid, which is subsequently converted to folic acid. PABA is involved in the synthesis of folic acid, an important precursor to the synthesis of nucleic acids. Sulfonamides are structural analogs of PABA and inhibit dihydropteroate synthetase.

Sulfonamides can enter into the reaction in place of PABA and compete for the active center of the enzyme. As a result, nonfunctional analogs of folic acid are formed, pre venting further growth of the bacterial cell. The inhibiting action of sulfonamides on bacterial growth can be counter acted by an excess of PABA in the environment (competitive inhibition). Animal cells cannot synthesize folic acid and must depend on exogenous sources. Some bacteria, similar to animal cells, are not inhibited by sulfonamides. Many other bacteria, however, synthesize folic acid, as mentioned earlier, and consequently are susceptible to action by sulfonamides.

Trimethoprim (3,4,5-trimethoxybenzylpyrimidine) inhibits dihydrofolic acid reductase 50,000 times more efficiently in bacteria than in mammalian cells. This enzyme reduces dihydrofolic to tetrahydrofolic acid, a stage in the sequence leading to the synthesis of purines and ultimately of DNA. Sulfonamides and trimethoprim each can be used alone to inhibit bacterial growth. If used together, they produce sequential blocking, resulting in a marked enhancement (synergism) of activity. Such mixtures of sulfonamide (five parts) plus trimethoprim (one part) have been used in the treatment of pneumocystis pneumonia, malaria, shigella enteritis, systemic salmonella infections, urinary tract infections, and many others.

Pyrimethamine also inhibits dihydrofolate reductase, but it is more active against the enzyme in mammalian cells and therefore is more toxic than trimethoprim. Pyrimethamine plus sulfonamide or clindamycin is the current treatment of choice in toxoplasmosis and some other protozoal infections.

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