Several of the drugs that interfere with metabolism are synthetic. These antimicrobials as a group do not originate from bacterial or fungal fermentations. Some were synthesized from aniline dyes, and others were originally isolated from plants. Although they have been largely re placed by antibiotics, a few of them remain essential to chemotherapy.
The most important drugs in this class are the sulfonamides, or sulfa drugs. Their name is derived from sulfanilamide, an early form of the drug (figure 1). These drugs function as metabolic analogs to block the synthesis of folic acid by bacteria (see figure 2). Dozens of these drugs have been developed, most of them narrow spectrum. Because of its solubility, sulfisoxazole is an effective choice for treating shigellosis, urinary tract infections, and certain protozoan infections. Silver sulfadiazine ointment and solution are prescribed for treatment of burns and eye infections. Another drug, trimethoprim, inhibits a second enzymatic step in the synthesis of folic acid. Because of this, trimethoprim is often given in combination with sulfamethoxazole to take advantage of the synergistic effect of the two drugs (Septra, Bactrim). This combination is one of the primary treatments for Pneumocystis jiroveci pneumonia (PCP), urinary tract infections, and otitis media.
Fig1. The structures of some sulfonamides. Boxed side chains attach at the —NH group of the nucleus. (a) Sulfacetamide, (b) sulfadiazine, and (c) sulfisoxazole.
Fig2. Competitive inhibition as a mode of action. (a) This example shows how sulfa drugs block a metabolic pathway used by bacteria to synthesize folic acid. Two different enzymes in the metabolic pathway are blocked, meaning that even if a bacterium could bypass one enzyme-catalyzed reaction, its progress would still be inhibited. (b) Formula of a sulfanilamide molecule compared alongside one of PABA. Note that, despite a similarity in overall shape, sulfa drugs cannot be used to make folic acid. (c) The sulfa drug molecules can insert into the active site in the enzyme that would ordinarily bind PABA. This will work only when the sulfa molecules are more prevalent and can outcompete PABA for available enzyme binding sites (keeping sites on the enzyme filled). Since little or no PABA can bind, the synthesis of folic acid will be inhibited. (a): Barry Chess/McGraw Hill
Sulfones are compounds chemically related to the sulfonamides but lacking their broad-spectrum effects. They still remain important as key drugs in treating Hansen’s disease (leprosy). The most active form is dapsone, usually given in combination with rifampin and clofazimine (an antibacterial dye) over long periods.
Antibiotics with Unique Mechanisms of Action
Although most new antibiotics are formulated from the drug classes that already exist, a few classes of drugs with novel actions against bacteria have been added to drug regimens. Medical experts are urging physicians to prescribe these medications only when no other drugs are available to slow the development of drug resistance.
Fosfomycin trimethamine is a phosphoric acid agent effective as an alternative treatment for urinary tract infections caused by enteric bacteria. It works by inhibiting an enzyme necessary for cell wall synthesis.
Synercid is an antibiotic from the streptogramin group of drugs that contains two active chemicals (quinupristin and dalfopristin) that together exert a synergistic action on certain bacteria. It has bactericidal effects against Staphylococcus and Enterococcus species that cause endocarditis and surgical infections and against resistant strains of Streptococcus. It is one of the main choices when other drugs are ineffective due to resistance. Synercid works by binding to sites on the 50S ribosome, inhibiting peptide transfer and elongation.
Daptomycin (Cubicin) is a lipopeptide directed mainly against gram-positive bacteria, acting to disrupt multiple aspects of mem brane function.
Another new class of drugs, the ketolides, is similar to macrolides like erythromycin but has a different ring structure. The main representative, telithromycin (Ketek), is used for respiratory tract infections caused by macrolide-resistant bacteria.
The oxazolidinone class of drugs operates using a unique mechanism, namely to inhibit the initiation of protein synthesis. It does this by interfering with the interaction between the mRNA and the two ribosomal subunits necessary for the initiation of translation. The two drugs in this class are linezolid (sold under the trade name Zyvox) and tedizolid (Sivextro). They are important alternative choices to treat infections caused by two prominent clinical pathogens, MRSA and vancomycin-resistant Enterococcus (VRE). Because they are synthetic and not found in nature, it is hoped that drug resistance will be slow to develop.
Bedaquiline is an antituberculosis drug that prevents the syn thesis of ATP in Mycobacterium, a novel mechanism of action. Sold under the brand name Sirturo, the drug is used only for the treatment of multi-drug resistant and extremely drug resistant Mycobacterium tuberculosis infections.
