In an in vitro study, double drug-resistant mutants of M.
smegmatis containing certain combinations of rpoB and gyrA
mutations (conferring resistance to RIF and ofloxacin, respective-
ly) were found to have higher fitness than at least one of the
corresponding single drug-resistant mutants.12 This means that,
in some cases, the overall cost of carrying multiple resistance
mutations can be less than what would be expected if those
mutations had independent (multiplicative) effects on fitness.
Further work is needed to confirm these findings (as the authors
were unable to exclude the acquisition of compensatory mutations
as a possible explanation for the observed phenotypes) and
elucidate the mechanisms behind them. Nonetheless, the
identification of the same combinations of rpoB and gyrA
mutations in clinical isolates of M.tb suggests that this might
represent another form of compensatory evolution with a
potential significant impact on the emergence of transmissible
MDR-TB strains.78 The acquisition of additional resistance
determinants, instead of further impairing fitness, can ameliorate
the deficits produced by resistance to other drugs. The resulting
strains will have both a selective advantage in the presence of