Quinolones and Fluoroquinolones

PHRM 306: Pharmacology II

Quinolones

• The first quinolone to be marketed (in 1965) was nalidixic acid

• Nalidixic acid and cinoxacin are classified as first-generation quinolones

• They are considered to be minor urinary tract disinfectants

• Thus, the quinolones were of little clinical significance

Quinolones

• Addition of a fluoro group to the 6-position of the basic nucleus greatly increased the biological activity

• Brought to the market in 1986, norfloxacin, the first of the second-generation quinolone

• More recent, quinolones are also referred to as the fluoroquinolones

Quinolones

• Following its introduction, intense competition ensued, more than a thousand second-, third-, and fourth generation analogues have now been made.

• Ciprofloxacin and levofloxacin dominate the worldwide fluoroquinolone market

Quinolones

• First generation– Nalidixic acid, Cinoxacin

• Second generation– Ciprofloxacin, Norfloxacin, Ofloxacin

• Third generation– Levofloxacin

• Fourth generation– Moxifloxacin

Mechanism of action

• The Escherichia coli chromosome is a single, circular molecule of approximately 1 mm in length, whereas the cell is only 1 to 3 µm long.

• Thus, the DNA molecule must be dramatically compacted in a conformationally stable way so that it can fit.

Mechanism of action

• Using the energy generated by adenosine triphosphate (ATP) hydrolysis, the molecule is progressively wound about itself in a positive supercoil.

• It also must be partially unwound so that the cell has access to the genetic information that it contains.

Mechanism of action

• Topoisomerases are enzymes that change the configuration or topology of DNA by a nicking, pass-through, and resealing mechanism.

Mechanism of action

• DNA gyrase is an enzyme responsible for introducing negative super coils into circular duplex DNA.

• Negative super coiling relieve the torsional stress of helical DNA, facilitates unwinding, and thereby, allows transcription and replication to occur.

Mechanism of action

• DNA topoisomerase IV decatenates (unties) enchained daughter DNA molecules produced through replication of circular DNA.

• Topoisomerase IV's second function in the cell is to relax positive super coils. It shares this role with DNA gyrase, which is also able to relax positive super coils.

Mechanism of action

• Inhibition of DNA gyrase and topoisomerase IV makes a cell's DNA inaccessible and leads to cell death, particularly if the cell must deal with other toxic effects at the same time.

• Humans shape their DNA with eukaryotic topoisomerase II (topo II), an analogous enzyme that does not bind quinolones at normally achievable doses, so the quinolones of commerce do not kill host cells.

Mechanism of action

• The fluoroquinolones enter the bacterium by passive diffusion through water-filled protein channels (porins) in the outer membrane.

• Once inside the cell, they inhibit the replication of bacterial DNA by interfering with the action of DNA gyrase (topoisomerase II) and topoisomerase IV during bacterial growth and reproduction.

FigureAction of Type II DNA topoisomerase.

• They do not change the DNA's primary sequence.

Mechanism of action

• In gram-negative organisms (for example, Escherichia coli), the inhibition of DNA gyrase is more significant than that of topoisomerase IV, whereas in gram-positive organisms (for example, the staphylococci), the opposite is true.

Resistance

Altered target: • Mutations in the bacterial DNA gyrase have

been associated with a decreased affinity for fluoroquinolones.

• Topoisomerase IV also undergoes mutations. • Resistance is frequently associated with

mutations in both gyrase and topoisomerase IV.

ResistanceDecreased accumulation: • Reduced intracellular concentration of the

drugs in the bacterial cell is linked to two mechanisms.

• One involves a decreased number of porin proteins in the outer membrane of the resistant cell, thereby impairing access of the drugs to the intracellular topoisomerases.

Resistance

Decreased accumulation: • The other mechanism is associated with an

energy-dependent efflux system in the cell membrane.

Pharmacokinetics

• Ingestion of the fluoroquinolones with sucralfate, antacids containing aluminum or magnesium, or dietary supplements containing iron or zinc can interfere with the absorption of these antibacterial drugs.

• Calcium and other divalent cations have also been shown to interfere with the absorption of these agents.

FigureEffect of dietary calcium on the absorption of ciprofloxaxin.

Drug drug interaction

FigureDrug interactions with fluoroquinolones.