An investigation of gene dosage reveals that increased sensitivity to D-cycloserine divergently impacts the transience of heteroresistance in <i>Escherichia coli</i>

Heteroresistance is a concern because heteroresistant strains escape clinical detection and facilitate treatment failure. Heteroresistant cells can produce stably resistant or transiently resistant populations, and enhanced understanding of genetic factors that influence the level of heteroresistance and its stability has the potential to improve treatment strategies. Here, we introduce the heteroresistance stability index, which is a quantitative metric of heteroresistance stability, and use it to analyze heteroresistance of <i>Escherichia coli</i> to D-cycloserine. We investigated how gene dosage of antibiotic target network components (transporter, enzymatic targets) influences heteroresistance and its stability and found diverging outcomes on stability for comparable declines in heteroresistance. Specifically, these results suggest that designing antibiotics to enter through multiple transporters or target multiple enzymes would reduce the emergence of stable resistance.