Quinolones

The problem of packaging the enormous circular chromosome of bacteria (>1 mm long) into the cell requires it to be twisted into a condensed ‘supercoiled’ state – a process aided by the natural strain imposed on a covalently closed double helix. The twists are introduced in the opposite sense to those of the double helix itself and the molecule is said to be negatively supercoiled. During the process of DNA replication, the DNA helicase and DNA polymerase enzyme complexes introduce positive supercoils into the DNA to allow progression of the replication fork. Re-introduction of negative supercoils involves precisely regulated nicking and resealing of the DNA strands, accomplished by enzymes called topoisomerases. One topoisomerase, DNA gyrase, is a tetramer composed of two pairs of α and β subunits, and the primary target of the action of nalidixic acid and other quinolones is the α subunit of DNA gyrase, although another enzyme, topoisomerase IV, is also affected. Indeed, in Gram-positive bacteria, topoisomerase IV seems to be the main target. This enzyme does not have supercoiling activity; it appears to be involved in relaxation of the DNA chain and chromosomal segregation.
Although DNA gyrase and topoisomerase IV are the primary determinants of quinolone action, it is believed that the drugs bind to enzyme–DNA complexes and stabilize intermediates with double-stranded DNA cuts introduced by the enzymes. The bactericidal activity of the quinolones is believed to result from accumulation of these drug stabilized covalently cleaved intermediates which are not subject to rescue by DNA repair mechanisms in the cell.
The coumarin antibiotic novobiocin acts in a complementary fashion to quinolones by binding specifically to the β subunit of DNA gyrase.

The quinolone antimicrobials comprise a group of synthetic substances possessing in common an N-1-alkylated 3-carboxypyrid-4-one ring fused to another aromatic ring, which itself carries other substituents. The first quinolone to be marketed (in 1965) was nalidixic acid. Nalidixic acid and cinoxacin are classified as first-generation quinolones based on their spectrum of activity and pharmacokinetic properties. While still available, they are considered to be minor urinary tract disinfectants that are effective primarily against certain susceptible Gram-negative bacteria. Thus, the quinolones were of little clinical significance until the discovery that the addition of a fluoro group to the 6-position of the basic nucleus greatly increased the biological activity.

Resistance to the quinolones is becoming more frequent and is associated with spontaneous mutations in two genes (gyrA and gyrB) that encode for the quinolone target protein, DNA gyrase. A single step mutation can lead to low-level resistance, whereas mutations in both genes lead to high-level resistance. This mechanism of resistance would be expected to produce cross-resistance within the class of quinolones. In addition, there are suggestions that resistance may be associated with an increase in drug efflux or a decrease in outer membrane permeability affecting drug influx. Such a mechanism of resistance would be expected to be more common in Gram-negative organisms with a more complex cell wall than in Gram-positive organisms with its cell envelope.

The pyridone-b-carboxylic acid derivatives or quinolones comprise a large and expanding number of synthetic compounds. Since the first analog, nalidixic acid, was synthesized in 1962, many types have been reported based on a few common structures: most are 1,8 naphthyridone or quinoline derivatives.
Changes to various parts of the molecules confer different properties and this is the basis of the variation in activity of various members of the group.
The first 4-quinolone, nalidixic acid, is a 1,8-naphthyridinone with a narrow spectrum of activity, chiefly against Enterobacteriaceae. Several compounds with improved antibacterial activity were subsequently synthesized. These included pipemidic acid, which expanded the spectrum to include weak activity against Pseudomonas aeruginosa, and piromidic acid, which exhibited useful activity against Staphylococcus aureus. Further development led to the discovery in the late 1970s of fluorine-substituted derivatives with much enhanced intrinsic activity against both organisms, a group now known as the fluoroquinolones. Numerous fluoroquinolones with altered pharmacokinetic properties and additional improvements in spectrum, including in some cases useful activity against Mycobacterium tuberculosis and M. leprae, became available in the next 30 years. Current research efforts are directed to overcome problems of resistance, which is increasingly encountered in both Gram-positive and Gram-negative bacteria.

The quinolones are rapidly bactericidal, largely as a consequence of inhibition of DNA gyrase and topoisomerase IV, key bacterial enzymes that dictate the conformation of DNA. The Escheri chi a 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. Using the energy generated by adenosine triphosphate (ATP) hydrolysis, the molecule is progressively wound about itself in a positive super coil.

The fluoroquinolones are well absorbed following oral administration, with excellent bioavailability. The maximum plasma concentration usually is reached within a few hours, and the drugs are moderately bound to plasma protein, leading to comparatively long half-lives. Earlier quinolones were rapidly excreted into the urine, which limited their therapeutic application to urinary tract infections, whereas the newer drugs are distributed to alveolar macrophages, bronchial mucosa, epithelial lining fluid, and saliva, improving the use in various systemic infections. Several studies have suggested that the ratio of mean peak plasma concentration to MIC and the 24-hour area under the curve to MIC may correlate with therapeutic outcomes. If this proves to be true, it could greatly help the clinician in choosing the appropriate drug and dosing schedule.

The quinolones therapeutically fall into one of four classifications. The specific drugs within each classification include nalidixic acid and cinoxin as first-generation agents, with utility limited to uncomplicated urinary tract infections. The second-generation quinolones include norfloxacin, lomefloxacin, enoxacin, ofloxacin, and ciprofloxacin. Whereas norfloxacin is used mainly for urinary tract infections (Enterobacter sp., Enterococcus sp., or Pseudomonas aerugi nosa), ciprofloxacin also is used for prostatitis, upper respiratory tract infections, bone infections, septicemia, staphylococcal and pseudomonal endocarditis, meningitis, sexually transmitted diseases (gonorrhea and chlamydia), chronic ear infections, and purulent osteoarthritis.

The quinolone class is associated with more side effects than the β-lactam and macrolide classes but, nonetheless, see very widespread medicinal use. Among the side effects associated with quinolones is a proconvulsant action, especially in epileptics, but this is mainly associated with the first-generation agents. Other CNS problems include hallucinations, insomnia, and visual disturbances. Some patients also experience diarrhea, vomiting, abdominal pain, and anorexia. These effects are most common with trovafloxacin. The quinolones are associated with erosion of the load-bearing joints of young animals.