KPC and Klebsiella pneumoniae: virulence and resistance converge

Summary

Klebsiella pneumonia is a contemporary emerging pathogen as more and more multidrug resistant (MDR) strains are being isolated in the clinic. The spectrum of illness associated with K. pneumoniae is vast: pneumonia, urinary tract infection, wound, liver abscess, and bloodstream infections. Since the early 2000s, isolates of K. pneumoniae resistant to carbapenems and carrying the KPC beta-lactamase (blaKPC) have become much more common. In addition, KPC-carrying K. pneumoniae strains tend to be resistant to other antimicrobial agents as well, severely limiting therapeutic options. Colistin is the treatment of Člast resortÉ for carbapenem-resistant K. pneumoniae. However, resistance to colistin (ColR) has been observed in the clinic, signifying that these infections are essentially untreatable.

We propose to use genome sequencing and gene expression analysis to evaluate two aspects of K. pneumoniae epidemiology and pathogenesis.

1) Colonizing vs. Invasive isolates. Identify genetic and clinical markers of virulence and transmissibility by comparison of KPC-positive colonizing K. pneumoniae isolates to those that have caused an infection (pneumonia, bloodstream infection, etc.) by genome sequencing and gene expression analysis (29 invasive and 21 colonizing strains from Cleveland and Detroit).
2) ColR Matched colistin susceptible and ColR isolates will be identified from patients that undergo colistin treatment based on in vitro susceptibility testing. Genome sequence will be used to find mutations and gene expression analysis to infer altered regulatory programs as have been observed in other ColR Gram-negative bacteria (5 pairs of isolates).

The resulting information will be a resource for the Klebsiella research community by greatly increasing the number whole genome sequences, by producing gene expression data that will serve as a baseline for future research and an initial snapshot of genome activity, and by illustrating the extent of change in clinical isolates over a two decade time span. It will also be the basis for development of molecular diagnostic assays to test for colistin resistance and other markers that predict likelihood that a colonizing isolate may cause infection.

All Publications that use data generated and/or are supported by the Sequencing Center at JCVI should acknowledge the sponsor as: This project has been funded in whole or part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract numbers N01-AI30071 and/or HHSN272200900007C.

White Paper Access

The initial white paper submitted can be downloaded here. Since white papers are not always approved exactly as submitted, this document may not exactly describe the final form of the project. Please contact gsc@jcvi.org if you have any questions.

Investigators and Collaborators

Mark Adams, PhD

Scientific Director, J.Craig Venter Institute

Robert A. Bonomo , PhD

Case Western Reserve University and Cleveland VAMC