Antimicrobial agents that target bacterial processes other than those already discussed include sulfonamides, trimethoprim, and nitrofurantoin.
Sulfonamides. The bacterial folic acid pathway pro duces precursors required for DNA synthesis (Figure 1). Sulfonamides target and bind to one of the enzymes, dihydropteroate synthase, and disrupt the folic acid pathway. Several different sulfonamide derivatives are available for clinical use. These agents are active against a wide variety of bacteria, including the gram positive and gram-negative (except P. aeruginosa) species. Sulfonamides are moderately toxic, causing vomiting, nausea, and hypersensitivity reactions. Sulfonamides are also antagonistic for several other medications, including warfarin, phenytoin, and oral hypoglycemic agents.
Fig1. Bacterial folic acid pathway indicating the target enzymes for sulfonamide and trimethoprim activity. (Modified from Katzung BG: Basic and clinical pharmacology, Norwalk, Conn, 1995, Appleton & Lange.)
Trimethoprim. Like the sulfonamides, trimethoprim targets the folic acid pathway. However, it inhibits a different enzyme, dihydrofolate reductase (see Figure 1). Trimethoprim is active against several gram-positive and gram-negative species. Frequently, trimethoprim is combined with a sulfonamide (usually sulfamethoxazole) into a single formulation to produce an antibacterial agent that can simultaneously attack two targets on the same folic acid metabolic pathway. This drug combination can enhance activity against various bacteria and may help prevent the emergence of bacterial resistance to a single agent. Toxicity is typically mild. Adverse side effects include gastrointestinal symptoms and allergic skin rashes. Patients with acquired immunodeficiency syndrome (AIDS) develop side effects more often than healthy individuals.
Nitrofurantoin. Nitrofurantoin consists of a nitro group on a heterocyclic ring. The mechanism of action of nitrofurantoin is diverse and multifaceted. This agent may have several targets involved in bacterial protein and enzyme synthesis. Nitrofurantoin is converted by bacterial nitroreductases to reactive intermediates that bind bacterial ribosomal proteins and rRNA, disrupting syn thesis of RNA, DNA, and proteins. Nitrofurantoin is used to treat uncomplicated urinary tract infections and has good activity against most of the gram-positive and gram-negative bacteria that cause infections at that site. Toxicity primarily consists of gastrointestinal symptoms, including diarrhea, nausea, and vomiting. Chronic pulmonary conditions may develop, including irreversible pulmonary fibrosis.
