Multidrug-resistant clinical isolates are common in certain pathogens, but rare in
others. This pattern may be due to the fact that mutations shaping resistance have
species-specific effects. To investigate this issue, we transferred a range of resistance-conferring
mutations and a full resistance gene into Escherichia coli and closely related bacteria.
We found that resistance mutations in one bacterial species frequently provide no
resistance, in fact even yielding drug hypersensitivity in close relatives. In depth
analysis of a key gene involved in aminoglycoside resistance (trkH) indicated that
preexisting mutations in other genes—intergenic epistasis—underlie such extreme differences
in mutational effects between species. Finally, reconstruction of adaptive landscapes
under multiple antibiotic stresses revealed that mutations frequently provide multidrug
resistance or elevated drug susceptibility (i.e., collateral sensitivity) only with
certain combinations of other resistance mutations. We conclude that resistance and
collateral sensitivity are contingent upon the genetic makeup of the bacterial population,
and such contingency could shape the long-term fate of resistant bacteria. These results
underlie the importance of species-specific treatment strategies.
