CLINICAL CASES
95
Nucleosome: Disk-shaped particles that consist of a core of histone protein
around which DNA is wrapped. They are a structural unit of chromatin.
Supercoiling: The act of DNA winding on itself as a result of unwinding
caused by replication forks.
Topoisomerase: Enzymes that control the amount of supercoiling in DNA.
Type I topoisomerases will cleave one strand of DNA to relieve super-
coiling, whereas type II topoisomerases will cleave both strands of the
DNA double helix.
D ISC U SSIO N
The quinolones are broad-spectrum synthetic antibiotic drugs that contain
the 4-quinolone ring (Figure 10-1). The first quinolone,
nalidixic acid,
was
synthesized in 1962. More recently, a family of fluoroquinolones has been
produced that contain a fluorine substituent at position 6 and a carboxylic acid
moiety in the 3 position of the basic ring structure. Rp R7, and X are substi-
tuted with different side chains for the purpose of increasing bioavailability of
the compound. A typical example of a fluoroquinolone is ciprofloxacin. The
quinolone antibiotics target bacterial DNA gyrase in many gram-negative bac-
teria such as
Escherichia coli, Klebsiella pneumoniae, Pseudomonas aerugi-
nosa,
and the like.
The normal biological functioning of DNA-like ribonucleic acid (RNA)
transcription and DNA replication occurs only if it is in the proper topologi-
cal state. In duplex DNA, the two strands are wound about each other once
every 10 bp, that is, once every turn of the helix. Double-stranded circular
DNA can form either negative supercoils when the strands are underwound
or positive supercoils when they are overwound (Figure 10-2). Negative
supercoiling introduces a torsional stress that promotes unwinding or separa-
tion of the right-handed B-DNA double helix, while positive supercoiling
overwinds such a helix.
Supercoiling is controlled by a remarkable group of enzymes known as
topoisomerases, which alter the topology of the circular DNA but not its
Figure 10-1. Structural formula for a fluoroquinolone. R1, R7, and X are side
chains.
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