Antibiotics that target RNA transcription or DNA replication to prevent new bacteria from being produced must be able to easily diffuse through bacterial membranes. Rifamycins, a subclass of ansamycins, can easily cross the bacterial cell wall and membrane and bind to bacterial DNA-dependent RNA polymerase, thereby suppressing the initiation of RNA transcription. Rifamycins inhibit RNA synthesis by directly blocking the path of the elongating RNA when the transcript becomes two to three nucleotides long (Figure 1). They do not interact with mammalian RNA polymerases but have broad-spectrum bactericidal effects on Gram-positive bacteria and some Gram-negative bacteria. Resistance to rifamycins mainly develops from mutations in the bacterial RNA polymerase.
Figure 1: Antibiotics interfere with DNA synthesis and replication.
Quinolones and fluoroquinolones target DNA synthesis by interfering with the coiling of DNA strands through inhibiting bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Topoisomerases relax supercoiled DNA and initiate transient breakages and rejoin phosphodiester bonds in superhelical turns of closed-circular DNA to allow the DNA strand to be replicated by DNA or RNA polymerases (Figure 1). Quinolones bind directly to the active site of the topoisomerase, and fluoroquinolones stabilize the enzyme-DNA complex to interrupt the religation step. Topoisomerases are present in both prokaryotic and eukaryotic cells, but quinolones are specific inhibitors of bacterial topoisomerases. Resistance to quinolones arises from mutations in DNA gyrase and topoisomerase IV, mutations that reduce drug accumulation via entry/efflux, and plasmids that produce Qnr proteins that bind to and protect both DNA gyrase and topoisomerase IV from inhibition.
Anthracyclines, which inhibit DNA replication and transcription in both bacterial and mammalian systems, are most often used as anticancer agents. They interact with the DNA-topoisomerase II complex or DNA itself through intercalation or forming covalent bonds and base modifications that require DNA repair or lead to apoptotic cell death (Figure 1). They attack rapidly growing malignant cells as well as normal cells, but because malignant cells are growing at a faster rate than the surrounding normal tissue, a higher percentage of cancer cells are harmed.
