P083

1:Swiss Tropical and Public Health Institute; 2:University of Basel

Studies in model organisms have shown that mutations conferring resistance to different antibiotics can interact epistatically. However, the nature and epidemiological consequences of such epistatic interactions have rarely been studied in human pathogens. Here we show that in Mycobacterium tuberculosis, one third of strains carrying mutations in RpoB and GyrA causing resistance to rifampicin and fluoroquinolones, respectively, interacted epistatically in vitro. In two instances, the double-mutants exhibited a higher fitness than the corresponding single mutants ─ a phenomenon known as positive sign epistasis. These two double-mutant genotypes together accounted for the large majority of highly drug-resistant M. tuberculosis in clinical settings, and exhibited a reduced proteome perturbance compared to less epidemiologically successful genotypes. Taken together, our findings highlight the relevance of epistasis for the evolution and spread of antimicrobial resistance.