Insights into the Metabolic Adaptations of a Carbapenem-Resistant Klebsiella pneumoniae Strain on Exposure to Sublethal Concentrations of Ertapenem

Klebsiella pneumoniae strains that are resistant to carbapenems are of great concern. Exposure to low concentrations of antibiotics may influence tolerance to antibiotics. Novel antibiotics and treatment options are thus needed, and this need is exacerbated by the rapid and global spread of antibiotic resistance. In this study, we determined the global proteome changes in a K. pneumoniae strain (CCUG 70747) carrying carbapenem resistance genes when exposed to low concentrations of ertapenem. Quantitative proteomics was achieved by the tandem mass tag labeling of peptides generated by trypsin proteolysis and mass spectrometry analysis. Bioinformatics analyses were used to observe changes in protein abundance, as well as the gene ontology (GO) terms and pathways associated with the differentially expressed proteins. The number of proteins detected with significant differential abundance were 87 at the highest concentration applied and 61 in the lowest concentration, all compared with the strain cultured without any antibiotics present. Several of these proteins, as well as the GO terms and pathways associated with the proteins, were linked to mechanisms of antibiotic resistance. However, this strain encodes a carbapenemase and other beta-lactamases, and thus, as expected, presented a reasonably modest adaptation in the global proteome upon exposure to the low concentrations of ertapenem applied. Nevertheless, our study identifies pathways that may lead to adaptation under sublethal concentrations of antibiotics leading to strains with higher tolerance.