Antibiotic resistance is a major threat to public health. Bacteria can become resistant by acquiring genes that counteract the action of antibiotics or by mutation of their targets. These targets are usually involved in essential processes and typically resistance mutations can impair bacterial growth in absence of antibiotics. However, combination of certain mutated alleles can result in an alleviation of this cost, thus favouring the acquisition of multiple resistances. This project aims to understand the mechanisms underlying the epistasis between resistance mutations. Decreased biosynthesis has been considered the main cause of the fitness cost associated to antibiotic resistance mutations. However, our preliminary results suggest the existence of additional causes, such as genomic instability or proteostasis imbalance. The study of these phenotypes in single and double resistant mutants of Escherichia coli will allow us to determine the nature of these epistatic interactions, as well as further understanding essential biological processes, and will provide information for the development of new treatments against multi-resistant infections.