Chemistry Mechanism of Action and Classification

All clinically approved quinolones in use in the United States contain a carboxylic acid moiety in the 3-position of the basic ring structure (the 4-quinolones). The 4-

quinolones inhibit DNA synthesis through their specific action on DNA gyrases, which are composed of two A and two B subunits. DNA subunits A (gyrase A gene) have a strand-cutting function to prevent overwinding (supercoiling) of the DNA strands during separation and eventual replication of the mirror strand. The A subunits are the site of action for the 4-quinolones. Recently a second target, unique to the fluoro-quinolones, has been identified as topoisomerase type IV. This enzyme is responsible for separating the daughter cells following replication.

The DNA gyrases and type IV topoisomerase both belong to the general class of DNA enzymes called topoisomerases. The effect of quinolones on these DNA enzymes is initially bacteriostatic but becomes bactericidal when bacteria are unable to repair the DNA lesions. These drug targets may be primary or secondary depending upon the organism; this observation can affect the bacterial potential for the development of drug resistance; this may require the use of another drug with a different specificity and spectrum of activity.

The quinolones are now often classified into generations, much like the cephalosporins. Each generation (first through fourth) has spectrum specificity and unique pharmacological properties, although there is considerable overlap: First, nalidixic acid and cinoxacin; second, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, and lomefloxacin; third. levofloxacin, sparfloxacin, gati-floxacin; and fourth, trovafloxacin and moxifloxacin. Several of the newer quinolones have been recently removed from the market as a result of QT prolongation and serious hematological and renal problems.

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