Fluoroquinolones, Metronidazole & DHFR Inhibitors

Fluoroquinolones, Metronidazole & DHFR Inhibitors

1. Overview & unifying theme

• These three drug families share a common downstream effect — they cripple bacterial DNA/nucleic-acid metabolism — but act at distinct nodes: sulfonamides/DHFR-inhibitors starve the cell of the one-carbon tetrahydrofolate cofactor needed for purine/thymidylate synthesis; fluoroquinolones poison the topoisomerases that manage DNA supercoiling and decatenation; nitroimidazoles generate reactive intermediates that directly fragment DNA (G&G 14e Ch.57, p.1137; Katzung 16e Ch.46, p.877).
• All exploit selective toxicity: the human cell either lacks the target (no DNA gyrase; uses preformed dietary folate so is insensitive to dihydropteroate synthase inhibition) or expresses a target with ~10³–10⁵-fold lower drug affinity (human DHFR vs bacterial DHFR; mammalian topoisomerase II vs bacterial gyrase) (G&G 14e Ch.57, pp.1138–42; KDT 8e Ch.51, p.756).
• Folate antagonists (sulfonamides + trimethoprim/pyrimethamine) and fluoroquinolones are wholly synthetic chemotherapeutic agents — not antibiotics of microbial origin — which historically made them less prone to pre-existing cross-resistance (KDT 8e Ch.51, pp.755, 759).
• Historically, sulfonamides (Prontosil, 1932–35) were the first systemically effective antibacterial chemotherapeutic agents in humans; Domagk received the 1938 Nobel Prize for demonstrating prontosil's protective effect in streptococcal infection (G&G 14e Ch.57, p.1137; KDT 8e Ch.51, p.755).