14.3 Mechanisms of antibacterial drugs  (Page 7/13)

Inhibitors of nucleic acid synthesis

Some antibacterial drugs work by inhibiting nucleic acid synthesis ( [link] ). For example, metronidazole is a semisynthetic member of the nitroimidazole family that is also an antiprotozoan. It interferes with DNA replication in target cells. The drug rifampin is a semisynthetic member of the rifamycin family and functions by blocking RNA polymerase activity in bacteria. The RNA polymerase enzymes in bacteria are structurally different from those in eukaryotes, providing for selective toxicity against bacterial cells. It is used for the treatment of a variety of infections, but its primary use, often in a cocktail with other antibacterial drugs, is against mycobacteria that cause tuberculosis . Despite the selectivity of its mechanism, rifampin can induce liver enzymes to increase metabolism of other drugs being administered (antagonism), leading to hepatotoxicity (liver toxicity) and negatively influencing the bioavailability and therapeutic effect of the companion drugs.

One member of the quinolone family, a group of synthetic antimicrobials, is nalidixic acid . It was discovered in 1962 as a byproduct during the synthesis of chloroquine , an antimalarial drug. Nalidixic acid selectively inhibits the activity of bacterial DNA gyrase, blocking DNA replication. Chemical modifications to the original quinolone backbone have resulted in the production of fluoroquinolones , like ciprofloxacin and levofloxacin , which also inhibit the activity of DNA gyrase. Ciprofloxacin and levofloxacin are effective against a broad spectrum of gram-positive or gram-negative bacteria, and are among the most commonly prescribed antibiotics used to treat a wide range of infections, including urinary tract infections, respiratory infections, abdominal infections, and skin infections. However, despite their selective toxicity against DNA gyrase, side effects associated with different fluoroquinolones include phototoxicity , neurotoxicity , cardiotoxicity , glucose metabolism dysfunction, and increased risk for tendon rupture.

Inhibitors of metabolic pathways

Some synthetic drugs control bacterial infections by functioning as antimetabolites , competitive inhibitors for bacterial metabolic enzymes ( [link] ). The sulfonamides ( sulfa drugs ) are the oldest synthetic antibacterial agents and are structural analogues of para -aminobenzoic acid (PABA), an early intermediate in folic acid synthesis ( [link] ). 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 ).