Stopping Replication, Transcription, and Folate Synthesis

Trapping the machines that copy and transcribe DNA Fluoroquinolones do not simply inhibit DNA gyrase; they convert it into a poison. DNA gyrase normally nicks the double helix, passes a strand through, and reseals the break to relieve the strain ahead of the replication fork. The drug stabilizes the enzyme-DNA cleavage complex, so the broken DNA ends stay bound to the enzyme and cannot be religated. Replication forks collide with these trapped complexes and generate double-strand breaks, and those breaks are lethal. Rifamycins take a different route: they bind the beta subunit of RNA polymerase and block the channel through which the nascent RNA exits, so transcription initiation is prevented. Both classes attack nucleic acid metabolism, but one poisons an enzyme and the other occludes a channel. Two sequential blocks in the folate pathway Sulfonamides mimic PABA and competitively inhibit dihydropteroate synthase. Trimethoprim inhibits dihydrofolate reductase, the enzyme that regenerates tetrahydrofolate. Because these are consecutive steps, the combination shuts the pathway down more completely than either drug alone. The selectivity comes from the fact that humans lack the enzymes for de novo folate synthesis and rely on dietary folate. Why the effect is usually bacteriostatic Blocking folate synthesis starves the cell of thymidine and purines, so DNA replication slows and growth stops. The cell is not immediately lysed, which is why sulfonamides and trimethoprim are classified as bacteriostatic rather than bactericidal.