The fluoroquinolones selectively inhibit topoisomerases II and IV, which are not found in mammalian cells. The enzymes, both tetramers comprising two A and two B subunits, are capable of catalysing a variety of changes in DNA topology.
FLUOROQUINOLONES
The fluoroquinolones
selectively inhibit topoisomerases II and IV, which are not found in mammalian cells.
The enzymes, both tetramers
comprising two A and two B
subunits, are capable of catalysing a variety of changes in DNA topology. The topoisomerases bind to the
chromosome at points where two separate double-stranded regions cross. This can be at a supercoiled region,
a knotted or a linked
(catenane) region. The A subunits (gyrA for topoisomerase II and parC for topoisomerase IV) cut both DNA strands
on one chain with a 4 base pair stagger; the other chain is passed
through the break which is then resealed. The B subunits
(gyrB for topoisomerase II and parE for topoisomerase IV) derive energy for the reaction by hydrolysis of ATP. The precise
details of the interaction are not clear
but it appears that the fluoroquinolones do not simply
eliminate enzyme function, they actively poison
the cells by trapping the topoisomerases as drug–enzyme–DNA
complexes in which double-stranded DNA breaks are held together by the enzyme protein alone. The enzymes are unable to reseal the DNA, with
the result that
the chromosome in treated cells becomes fragmented. The number of fragments (approximately 100 per cell)
is comparable to the
number of supercoils in the chromosome. The action of the fluoroquinolones probably triggers secondary responses in the cells which
are responsible for death. One notable morphological effect of
fluoroquinolone treatment of Gram-negative rod-shaped organisms is the formation of filaments. In Gram-positive cocci
topoisomerase IV may be the more
important target for fluoroquinolone action.
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