History shapes regulatory and evolutionary responses to tigecycline in two reference strains of .

Evolutionary history encompasses both genetic and phenotypic bacterial differences; however, the extent to which this history influences drug response and antimicrobial resistance (AMR) adaptation remains unclear. Historical contingencies arise when elements from an organism's past leave lasting effects on the genome, altering the paths available for adaptation. Here, we compare two diverging reference strains of , representative of archaic and contemporary infections, to study the impact of deep historical differences shaped by decades of adaptation in varying antibiotic and host pressures. We evaluated these effects by comparing immediate and adaptive responses to the last-resort antibiotic, tigecycline (TGC). The strains demonstrated divergent transcriptional responses, suggesting that baseline transcript levels may dictate global responses to antibiotics. Experimental evolution in TGC revealed clear differences in population dynamics, with hard sweeps in populations founded by one strain and no mutations reaching fixation in the other strain. AMR was acquired through predictable mechanisms of increased efflux and drug target modification; however, efflux targets were dictated by strain background. Genetic adaptation may outweigh historic differences in transcriptional networks, as evolved populations no longer show transcriptomic signatures of drug response. Importantly, fitness-resistance trade-offs were only observed in lineages evolved from the archaic strain, while the contemporary reference isolate suffered no fitness defects. This suggests that decades of adaptation to antibiotics resulted in pre-existing compensatory mechanisms in the more contemporary isolate, an important example of a beneficial effect of historical contingencies.