Translation Bottlenecks and Bacterial Growth Laws Predict Combined Antibiotic Action

Fast growth of bacteria requires a well-orchestrated translation machinery which is modulated internally by translation factors and perturbed by certain antibiotics (translation inhibitors). Coupling of the growth rate and ribosome synthesis results in ribosomal growth laws - relations connecting ribosome concentration to the growth rate. Joint effects of antibiotic combinations range from synergistic to antagonistic and are hard to predict, as the mechanisms of these interactions remain unknown. We hypothesize that the interactions between translation inhibitors arise from kinetic properties of the antibiotics together with the interplay of different stages in which ribosomes are halted. To test how halting of the ribosomes affects the efficacy of antibiotics, we constructed bacterial strains in which we imposed artificial bottlenecks in translation by controlling the abundance of different translation factors. Measuring the change in the antibiotic efficacy for a given limiting step, we used the growth law-based mathematical model to predict the interactions between various translation inhibitors. These findings offer new insights into the mechanisms of antibiotic interactions and translation itself and suggest a novel way of designing new antibiotic therapies.