Simple SummaryThe concept of “structural epistasis” expresses the emergence of new phenotypes which are not based on changes in the products and functions of genes, but on the changes in the physical–mechanical interactions between biological structural pieces and components of the bacterial cell architecture. These interactions are fostered by primary physical changes in the shape and size of the pieces or in spatial (topological) alterations driven by changes in their quantity or local density of the cell compartments, and might have consequences on antibiotic resistance phenotypes.AbstractEpistasis refers to the way in which genetic interactions between some genetic loci affect phenotypes and fitness. In this study, we propose the concept of “structural epistasis” to emphasize the role of the variable physical interactions between molecules located in particular spaces inside the bacterial cell in the emergence of novel phenotypes. The architecture of the bacterial cell (typically Gram-negative), which consists of concentrical layers of membranes, particles, and molecules with differing configurations and densities (from the outer membrane to the nucleoid) determines and is in turn determined by the cell shape and size, depending on the growth phases, exposure to toxic conditions, stress responses, and the bacterial environment. Antibiotics change the bacterial cell’s internal molecular topology, producing unexpected interactions among molecules. In contrast, changes in shape and size may alter antibiotic action. The mechanisms of antibiotic resistance (and their vectors, as mobile genetic elements) also influence molecular connectivity in the bacterial cell and can produce unexpected phenotypes, influencing the action of other antimicrobial agents.