The resistance mechanism determines physiological adaptation of Escherichia coli during growth with sublethal concentrations of carbapenem

The increase in carbapenem-resistant Enterobacteriaceae challenges effective treatment during infection and poses a serious health threat globally. Factors governing resistance in those bacteria are manifold, and despite ample research efforts, underlying molecular mechanisms are still only partly understood. Furthermore, little is known on (eco)physiological consequences from resistance acquisition originating from distinct mechanisms in respective bacteria.In this study, we examined physiological adaptation of Escherichia coli clinical isolates exhibiting two distinct resistance mechanisms – either carrying a carbapenemase (n=4; CARB) or alterations of porin-coding genes (n=6; POR) – during growth with sublethal concentrations of ertapenem in chemostat culture. Basic growth parameters based on flow-cytometric analyses and global gene expression patterns using RNA-Seq were recorded. We demonstrate that strategies to deal with the antibiotic are distinct between strains of the two groups, where (increased) expression of carbapenemases was the only response in CARB, whereas wide-spread alterations in gene-expression that promoted a survival-like phenotype, including induction of the stringent response, was observed in POR. Their response was accompanied with “costs of resistance” resulting in reduced growth efficiencies that are intrinsic to POR and were also observed during growth without antibiotic challenge, however, at lower levels. All strains showed similar MIC values and did not form phylogenetic groups indicating that results cannot be attributed to distinct resistance levels or phylogenetic relationships, but are indeed ascribed to the resistance mechanisms.Results can assist the development of precision treatment targeting mechanistic (sub)groups and to take specific measures in order to restrict the spread of antibiotic resistance.