Replication mechanisms and target enzymes
During the doubling of bidirectional bacterial DNA, excessive twisting—supercoils generating mechanical stress—occurs ahead of the replication fork. Furthermore, upon completion of replication, circular chromosomes form linked rings known as catenanes.
To resolve these obstacles, bacteria require topoisomerases:
- In Gram-negative bacteria, the primary target is DNA gyrase (a type II topoisomerase), which neutralizes positive supercoils via double-strand breaks.
- In Gram-positive bacteria, topoisomerase IV plays the main role, ensuring decatenation of daughter DNA rings for their distribution into cells.
Molecular mechanism of drug action
Fluoroquinolones interfere with enzyme function at the DNA cleavage stage:
- The drugs stabilize the DNA–enzyme complex, inhibiting it before the passage of the second segment.
- Low concentrations cause reversible inhibition (bacteriostatic effect).
- High (therapeutic) concentrations convert topoisomerases into DNA-damaging agents: the enzymes cause double-strand breaks in the polymer, triggering cell death (bactericidal effect).
The drugs are safe for the macroorganism because human topoisomerase II is inhibited only at ultra-high concentrations.
Spectrum of activity and pharmacokinetics
First-generation fluoroquinolones have a broad antibacterial spectrum with predominant activity against Gram-negative flora (, , , , , , ).
- Additional coverage: includes Gram-positive cocci and intracellular microorganisms (, , ).
- Tuberculosis: ciprofloxacin, ofloxacin, and lomefloxacin are active against Mycobacterium tuberculosis.
- Limitations: the drugs do not act on anaerobes.
- Pharmacokinetics: upon oral administration, they achieve high concentrations in blood and tissues regardless of food intake and penetrate inside cells.
Mechanisms of resistance
Bacterial resistance develops relatively slowly through the following mechanisms:
- Chromosomal mutations in topoisomerase genes (alteration of the target structure).
- Decreased cell membrane permeability due to suppressed porin expression.
- Activation of efflux pumps that actively transport the drug out of the cell.
Floxacins versus gyrase: breaking the chain of the infection!
Class and exam questions
What are the main targets of fluoroquinolones in bacteria?
The main targets are DNA gyrase (in Gram-negative bacteria) and topoisomerase IV (in Gram-positive bacteria).
What accounts for the transition from bacteriostatic to bactericidal action?
Low drug concentrations cause reversible enzyme inhibition (bacteriostasis), whereas high therapeutic concentrations convert topoisomerases into DNA-damaging agents, leading to irreversible double-strand breaks and cell death.
Do first-generation fluoroquinolones act on anaerobic microorganisms?
No, these drugs are not active against anaerobes.
What else to study on this topic
- Physics of DNA replication: supercoils and catenanes
- Catalytic cycle of topoisomerases: stages from binding to religation
- Dose-dependent effects and the bacterial SOS response
- Molecular mechanisms of resistance: porins and efflux pumps
- Tissue distribution and features of intracellular action
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