Characterization of genome-wide transpositions induced by colistin exposure in multi-drug-resistant Klebsiella pneumoniae

Abstract

Colistin is one of the last-line antibiotics against multi-drug-resistant (MDR) gram-negative pathogens, such as Klebsiella pneumoniae. Using long-read sequencing, we observed remarkable genome-wide transposition events in MDR K. pneumoniae exposed to colistin in patients receiving treatment for respiratory infections or as part of selective decolonization strategies and further confirmed these on in vitro selection experiments. These data add yet another dimension to the role of antibiotics in mediating specific processes in bacteria beyond antibiotic resistance.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02208154.

Keywords: antibiotic resistance; colistin; insertion sequence elements; muti-drug resistant Klebsiella penumoniae.

Fig 1

Condensed whole-genome synteny map of MDR K. pneumoniae strains isolated pre- (3319S) and post-colistin treatment (3359R) from a Greek patient and a derivative strain from 3319S (3319-10R, colistin MIC 64 mg/L) generated in vitro by passaging 3319S under colistin pressure (A). Visualization of selected genomic regions of strain 3319-10R displaying the ISKpn1 and ISKpn26 insertions in the promoter region of the pga operon (top) and the ISKpn60 insertion in the PilZ-domain encoding region of mrkH (bottom). Both genome regions are associated with biofilm formation in K. pneumoniae (B).

Fig 2

Heatmap demonstrating IS element amplification in the colistin-resistant K. pneumoniae strain 3359R compared to the colistin-susceptible 3319S and strains generated by passaging 3319S under colistin pressure (3319-2R, colistin MIC 64 mg/L; 3319-4R, colistin MIC 64 mg/L; 3319-10R, colistin MIC 64 mg/L).