Selection of Resistant Bacteria at Very Low Antibiotic Concentrations

TLDR

Widespread antibiotic use selects for resistance, yet the role of the much lower concentrations found in many environments remains largely unclear. The authors employed a mathematical model to predict how rapidly de novo mutants selected at sub‑MIC antibiotic concentrations would take over a susceptible bacterial population. Highly sensitive competition experiments showed that even concentrations hundreds of times below the MIC can select for resistant bacteria and de novo mutants, underscoring the importance of low environmental antibiotic levels in resistance enrichment and maintenance.

Abstract

The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.