A Revised Ribosome-Antibiotic Model with Proportional Feedback Synthesis Explains Recovery from Translation Inhibition.

Abstract

Antibiotic resistance remains an urgent challenge in medicine, shaped not only by genetic mechanisms but also by adaptation of bacteria under drug exposure. Comprehending these constraints requires integrating how translational capacity, nutrient supply, and global feedback determine recovery and survival. In this work, we integrate a refined mechanistic model of reversible protein synthesis inhibition with experimental measurements of bacterial growth. Our framework incorporates a metabolically limited recovery phase and a proportional feedback controller that links amino acid supply to ribosome synthesis. These refinements resolve unrealistic recovery dynamics predicted by earlier formulations and capture the physiological adaptation of Escherichia coli observed under pulse-dose exposure to tetracycline in both glucose- and glycerol-based media. The resulting framework unifies steady-state and transient antibiotic responses, explaining how metabolic limitation and feedback regulation shape cellular recovery following translational stress. Clinically, the model supports high-intensity antibiotic pulses of limited duration (on the order of several hours) that maximize inhibition while minimizing the selective window for resistance, providing a quantitative rationale for pulse- and intermittent-dosing strategies.