Fluoroquinolones exert their bactericidal effect primarily by inhibiting which bacterial enzyme?

Explanation

## Mechanism of Action of Fluoroquinolones **Key Point:** Fluoroquinolones are bactericidal agents that inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, preventing DNA unwinding and replication. ### Molecular Target and Mechanism 1. **DNA Gyrase (Topoisomerase II)** - Primary target in Gram-negative bacteria - Catalyzes negative supercoiling of DNA - Essential for DNA replication and transcription - Inhibition leads to accumulation of DNA breaks 2. **Topoisomerase IV** - Primary target in Gram-positive bacteria - Responsible for decatenation (separation) of daughter DNA strands - Inhibition prevents chromosome segregation 3. **Mechanism of Bactericidal Action** - Fluoroquinolone binds to the enzyme–DNA complex - Prevents religation of DNA strands - Accumulation of double-strand breaks - Rapid cell death (bactericidal, not bacteriostatic) **High-Yield:** The differential targeting of DNA gyrase vs. topoisomerase IV explains the spectrum differences: - **Ciprofloxacin**: Better activity against Gram-negative organisms (targets DNA gyrase) - **Levofloxacin, Moxifloxacin**: Better Gram-positive coverage (target topoisomerase IV) **Mnemonic:** **FQ = DNA Topoisomerase Inhibitors** (Fluoroquinolones = Fluorinated Quinolones that block Topoisomerases) **Clinical Pearl:** Unlike aminoglycosides (protein synthesis inhibitors) or macrolides (ribosomal inhibitors), fluoroquinolones do not require active protein synthesis for bactericidal activity — they work even on stationary-phase bacteria. **Warning:** Do not confuse fluoroquinolone targets with: - ~~RNA polymerase~~ (inhibited by rifampicin) - ~~Peptidyl transferase~~ (inhibited by aminoglycosides, macrolides, tetracyclines) - ~~Dihydrofolate reductase~~ (inhibited by trimethoprim, methotrexate)