Inhibition of Nucleic Acid Synthesis by Antibiotics

Quinolones are a key group of antibiotics that interfere with DNA synthesis by inhibiting topoisomerase, most frequently topoisomerase II (DNA gyrase), an enzyme involved in DNA replication. DNA gyrase relaxes supercoiled DNA molecules and initiates transient breakages and rejoins phosphodiester bonds in superhelical turns of closed-circular DNA. This allows the DNA strand to be replicated by DNA or RNA polymerases. The fluoroquinolones, second-generation quinolones that include levofloxacin, norfloxacin, and ciprofloxacin, are active against both Gram-negative and Gram-positive bacteria.

Topoisomerases are present in both prokaryotic and eukaryotic cells, but the quinolones are specific inhibitors of bacterial topoisomerase II. Inhibitors that are effective against mammalian topoisomerases, such as irinotecan and etoposide, are used as antineoplastic drugs to kill cancer cells.

Rifampicin blocks initiation of RNA synthesis by specifically inhibiting bacterial RNA polymerase. It does not interact with mammalian RNA polymerases, making it specific for Gram-positive bacteria and some Gram-negative bacteria.

Some antibiotics that interfere with RNA synthesis by inhibiting RNA polymerase, such as doxorubicin and actinomycin D (dactinomycin), are not specific for bacteria and interfere with both bacterial and mammalian systems. These are most often used as antineoplastic and antitumor drugs, attacking rapidly growing malignant cells as well as normal cells. Because cancerous cells are growing at a faster rate than surrounding normal tissue, a higher percentage of malignant cells are attacked by cytotoxic drugs. However, antitumor drugs cannot differentiate between malignant cells and fast-dividing normal cells such as those of the intestinal epithelium or hair follicles.