The primary antimicrobial agents that target DNA metabolism are the fluoroquinolones and metronidazole.
Fluoroquinolones. Fluoroquinolones, also often simply referred to as quinolones, are derivatives of nalidixic acid, an older antibacterial agent. The structures of two quinolones, ciprofloxacin and ofloxacin, are shown in Figure 1. These agents bind to and interfere with DNA gyrase enzymes involved in the regulation of bacterial DNA supercoiling, a process essential for DNA replication, recombination, and repair. The newer fluoroquinolones also inhibit topoisomerase IV. Topoisomerase IV functions very similarly to DNA gyrase, unlinking DNA after replication. The fluoroquinolones are potent bactericidal agents and have a broad spectrum of activity that includes gram-negative and gram-positive organisms. The fluoroquinolones target the DNA gyrase in gram negative organisms and topoisomerase IV in gram positive organisms. Because these agents interfere with DNA replication and therefore cell division, the drugs are bacteriocidal. However, the spectrum of activity varies with the individual quinolone agent. Toxicity varies with a variety of factors. Tendinitis and rupture of the Achilles tendon have been associated with fluoroquinolone treatment in the general population, and the risk is greater in older patients.
Fig1. Structures of the fluoroquinolones ciprofloxacin and ofloxacin. (Modified from Katzung BG: Basic and clinical pharmacology, Norwalk, Conn, 1995, Appleton & Lange.)
Metronidazole. The exact mechanism of metronidazole’s antibacterial activity is related to the presence of a nitro group in the chemical structure. The nitro group is reduced by a nitroreductase in the bacterial cytoplasm, generating cytotoxic compounds and free radicals that disrupt the host DNA. Activation of metronidazole requires reduction under conditions of low redox potential, such as are found in anaerobic environments. Therefore, this agent is most potent against anaerobic and microaerophilic organisms, notably those that are gram negative. The drug is also effective in the treatment of protozoans, including Trichomonas and Giardia spp. and Entamoeba histolytica. Because susceptibility testing is not routinely performed on anaerobes, resistance is under reported. An emerging resistance to metronidazole is creating difficulties associated with bacterial diagnostics and treatments. Toxicity is low. Adverse side effects generally include mild gastrointestinal symptoms.
Rifamycin. Rifamycins, which include the drug rifampin (also known as rifampicin), are semisynthetic antibiotics that bind to the enzyme DNA-dependent RNA polymerase and inhibit synthesis of RNA. Because rifampin does not effectively penetrate the outer membrane of all gram-negative bacteria, activity against these organisms is decreased compared to the drug’s activity in gram positive bacteria. In addition, spontaneous mutation, resulting in the production of rifampin-insensitive RNA polymerases, occurs at a relatively high frequency of mutation. Therefore, rifampin is typically used in combination with other antimicrobial agents. Rifampin’s side effects include gastrointestinal symptoms and hyper sensitivity reactions.
