Abstract
Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance—yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time-dependent. Here, we use a theoretical model, previously applied to steady-state bacterial growth, to predict the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding (‘low-affinity antibiotic’) or, in contrast, irreversible transport and/or high affinity ribosome binding (‘high-affinity antibiotic’). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, and can show a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance.
Highlights
Modern clinical practice relies on the use of antibiotics to combat bacterial infections, yet our knowledge of how antibiotics inhibit bacteria is surprisingly incomplete
We have studied the dynamical response of the bacterial growth rate to sustained and transient antibiotic treatment, for ribosome-targeting antibiotics
In previous work [8], this model has been shown to predict qualitatively different steady-state behaviour for two classes of ribosome-targeting antibiotics: “low-affinity” antibiotics which bind to ribosomes with low affinity and/or are transported reversibly across the cell boundary, and “high-affinity” antibiotics which bind with high affinity and/or are transported irreversibly
Summary
Modern clinical practice relies on the use of antibiotics to combat bacterial infections, yet our knowledge of how antibiotics inhibit bacteria is surprisingly incomplete. Potentially clinically relevant, differences in the dynamical response of bacterial growth to antibiotic treatment, depending on the molecular parameters for antibiotic-ribosome binding and transport of antibiotic across the bacterial cell boundary. This work showed that contrasting experimental observations for the growth-medium dependent efficacy of different ribosome-targeting antibiotics can be reproduced by a simple mathematical model that takes account of the molecular processes of antibiotic-ribosome binding and antibiotic transport across the cell boundary, as well as the physiological processes of cell growth and ribosome synthesis [8]. We suggest ways in which these predictions could be tested experimentally and comment on their potential clinical relevance
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