Antimicrobial resistance (AMR) is a major threat to public health. The fitness of AMR strains is determined partially by epistasis - resistance mutations may have different effects on different genetic backgrounds. I investigated the effects of genotype on the fitness of AMR in E. coli. Quinolone resistance alleles of the gyrA gene (S83L, D87N, and S83L-D87N) were transferred into a collection of knockout strains. Genetic interactions that affected fitness, both positively and negatively, were common and a variety of synthetic lethal/sick interactions were found. A number of the lethal interactors were involved in DNA repair and replication, much like gyrA itself. In subsequent validation assays, 21 of 33 strains showed a deficit in at least one fitness-related phenotype. The interactions identified here may elucidate gene functionality, and identification of synthetic lethal interactions of AMR mutations may lead to drug targets that can specifically kill resistant bacteria.