Fluoroquinolones (FQ) form the backbone in experimental treatment regimens against
drug-susceptible tuberculosis. However, little is known on whether the genetic variation
present in natural populations of Mycobacterium tuberculosis (Mtb) affects the evolution
of FQ-resistance (FQ-R). To investigate this question, we used nine genetically distinct
drug-susceptible clinical isolates of Mtb and measured their frequency of resistance
to the FQ ofloxacin (OFX) in vitro. We found that the Mtb genetic background led to
differences in the frequency of OFX-resistance (OFX-R) that spanned two orders of
magnitude and substantially modulated the observed mutational profiles for OFX-R.
Further, in vitro assays showed that the genetic background also influenced the minimum
inhibitory concentration and the fitness effect conferred by a given OFX-R mutation.
To test the clinical relevance of our in vitro work, we surveyed the mutational profile
for FQ-R in publicly available genomic sequences from clinical Mtb isolates, and found
substantial Mtb lineage-dependent variability. Comparison of the clinical and the
in vitro mutational profiles for FQ-R showed that 51% and 39% of the variability in
the clinical frequency of FQ-R gyrA mutation events in Lineage 2 and Lineage 4 strains,
respectively, can be attributed to how Mtb evolves FQ-R in vitro. As the Mtb genetic
background strongly influenced the evolution of FQ-R in vitro, we conclude that the
genetic background of Mtb also impacts the evolution of FQ-R in the clinic.
