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What you notice is that
moxifloxacin selects gyrase mutants and levofloxacin selects topoisomerase IV mutants, but
only at high concentrations. At low concentrations the mutants lack the classic mutations.
While we have not defined the mutations responsible for the low-level resistance, our
current guess is that they are involved in drug efflux. An interesting feature of this
table is that the frequency at which gyrase mutants are recovered with moxifloxacin is
about 1000 times lower than topoisomerase IV mutants with levofloxacin. This difference
may be due to the genetics of resistance for the two targets. Gyrase-mediated resistance
is recessive while topoisomerase IV-mediated resistance is codominant. Recessive mutants
remain susceptible to the lethal action of the drug until all sensitive protein has been
replaced by new, resistant protein. Thus new gyrase mutants will be rarer than
topoisomerase IV mutants. Another factor could be the 10-fold greater activity of
moxifloxacin at killing resistant mutants. In either case fluoroquinolones that
preferentially target gyrase are less likely to enrich resistant mutants. |
