Fernando Baquero, Jose-Luis Martínez, Alvaro Sanchez, Miguel D. Fernandez-de-Bobadilla, Alvaro San-Millán, Jeronimo Rodríguez-Beltrán

Epistasis refers to how genetic interactions between some genetic loci affect phenotypes and fitness. In this study, we propose the concept “structural epistasis” to emphasize the role of the variable physical interactions between molecules located at particular spaces inside the bacterial cell in the emergence of novel phenotypes. The architecture of the bacterial cell (typically a gram-negative), which consists of concentrical layers of membranes, particles, and molecules with differing con-figurations and densities (from the outer membrane to the nucleoid) determines and is at its turn determined by the cell´s shape and size, depending on the growth phases, and exposure to toxic conditions, stress responses, and the bacterial environment. Antibiotics change the bacterial cell’s internal molecular topology, producing unexpected interactions among molecule. In contrast, changes in shape and size might 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.