Metabolic constraints on the evolution of antibiotic resistance

Despite our continuous improvement in understanding antibiotic resistance,
the interplay between natural selection of resistance mutations and the
environment remains unclear. To investigate the role of bacterial metabolism
in constraining the evolution of antibiotic resistance, we evolved Escherichia
coli growing on glycolytic or gluconeogenic carbon sources to the selective
pressure of three different antibiotics. Profiling more than 500 intracellular
and extracellular putative metabolites in 190 evolved populations revealed
that carbon and energy metabolism strongly constrained the evolutionary
trajectories, both in terms of speed and mode of resistance acquisition. To
interpret and explore the space of metabolome changes we developed a
novel constraint-based modeling approach using the concept of shadow
prices. This analysis, together with genome resequencing of resistant populations, identified condition-dependent compensatory mechanisms of
antibiotic resistance such as the shift from respiratory to fermentative
metabolism of glucose upon overexpression of efflux pumps. Moreover,
metabolome-based predictions revealed emerging weaknesses in resistant
strains, such as the hypersensitivity to fosfomycin of ampicillin resistant
strains. Overall, resolving metabolic adaptation throughout antibiotic-driven
evolutionary trajectories opens new perspectives in the fight against
emerging antibiotic resistance.