Molecular dissection of the evolution of carbapenem-resistant multilocus sequence type 258 Klebsiella pneumoniae

Abstract

Infections caused by drug-resistant bacteria are a major problem worldwide. Carbapenem-resistant Klebsiella pneumoniae, most notably isolates classified as multilocus sequence type (ST) 258, have emerged as an important cause of hospital deaths. ST258 isolates are predominantly multidrug resistant, and therefore infections caused by them are difficult to treat. It is not known why the ST258 lineage is the most prevalent cause of multidrug-resistant K. pneumoniae infections in the United States and other countries. Here we tested the hypothesis that carbapenem-resistant ST258 K. pneumoniae is a single genetic clone that has disseminated worldwide. We sequenced to closure the genomes of two ST258 clinical isolates and used these genomes as references for comparative genome sequencing of 83 additional clinical isolates recovered from patients at diverse geographic locations worldwide. Phylogenetic analysis of the SNPs in the core genome of these isolates revealed that ST258 K. pneumoniae organisms are two distinct genetic clades. This unexpected finding disproves the single-clone hypothesis. Notably, genetic differentiation between the two clades results from an ∼215-kb region of divergence that includes genes involved in capsule polysaccharide biosynthesis. The region of divergence appears to be a hotspot for DNA recombination events, and we suggest that this region has contributed to the success of ST258 K. pneumoniae. Our findings will accelerate research on novel diagnostic, therapeutic, and vaccine strategies designed to prevent and/or treat infections caused by multidrug resistant K. pneumoniae.antibiotic resistance | carbapenemase | Enterobacteriaceae | plasmid

Carbapenem-Resistant Klebsiella pneumoniae Strains Exhibit Diversity in Aminoglycoside-Modifying Enzymes, Which Exert Differing Effects on Plazomicin and Other Agents

“…Indeed, ST258 strains were distinct by genotypes (presence of particular molecular mechanisms of antimicrobial resistance) and/or phenotypes (antimicrobial susceptibility profiles). Our data add to a growing body of evidence that ST258 K. pneumoniae strains are highly heterogenous, despite being considered clonal by conventional molecular epidemiologic criteria (5,(26)(27)(28)(29)(30). We previously showed that differences in ompK36 genotypes and gene expression among ST258 strains at our center predict susceptibility or resistance to carbapenemcolistin combinations during time-kill assays (27,29).…”

“…We previously showed that differences in ompK36 genotypes and gene expression among ST258 strains at our center predict susceptibility or resistance to carbapenemcolistin combinations during time-kill assays (27,29). Recent studies from our group and others have demonstrated striking diversity in the core genome of ST258 K. pneumoniae strains, including strains recovered from patients at single centers or longitudinally from the bloodstreams of individual patients (26,28). Variations in plasmid content and number are associated with differences in multidrug resistance patterns (26).…”

Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae , an urgent threat to public health

“…Several recent genomic analyses indicate that sequence type (ST) 258 is a recombinant strain that has undergone capsular exchange since its emergence as a cause of KPC outbreaks (28)(29)(30). However, little attention has been paid to other MDR clones, which also are common and can spread carbapenem resistance (31).…”

Evaluation of Antibiotic Resistance Patterns of Clinical Klebsiella pneumoniae Isolates from Educational Hospitals in Zahedan, Iran

“…Because of the genetic variations in the bacterial strains and the difference in the frequency of antibiotic use, a drug resistance rate varies widely in different regions of the world. Hence, identifying important and common hospital pathogens and determining the exact pattern of antibiotic resistance could be of use for the control of outbreaks and reduction of treatment costs (18,19). The resistance rates reported in studies from different provinces of Iran have been inconsistent.…”