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CrrB Positively Regulates High-Level Polymyxin-Resistance and Virulence in Klebsiella pneumoniae

64 Pages Posted: 14 Jul 2020 Publication Status: Published

See all articles by Thomas Howe McConville

Thomas Howe McConville

Columbia University - Division of Infectious Diseases

Medini K. Annavajhala

Columbia University - Department of Medicine

Marla J. Giddins

Columbia University - Division of Infectious Diseases

Nenad Macesic

Monash University - Department of Infectious Diseases

Carmen M. Herrera

Departments of Infectious Diseases, College of Veterinary Medicine, University of Georgia

Felix D. Rozenberg

Columbia University - Division of Infectious Diseases

Gitanjali L. Bhushan

Columbia University - Division of Pediatric Critical Care

Danielle Ahn

Columbia University - Department of Pediatrics

Filippo Mancia

Columbia University - Department of Physiology

Michael Trent

University of Georgia - Department of Infectious Diseases

Anne-Catrin Uhlemann

Columbia University - Department of Medicine

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Abstract

Polymyxin resistance (PR) threatens the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. PR frequently arises through the chemical modification of the lipid-A portion of lipopolysaccharide. Various mutations have been implicated in PR, but few have been functionally validated. We therefore adapted a CRISPR-Cas9 system to CRKP to elucidate how mutations in clinical CRKP isolates lead to PR. Specifically we demonstrate that CrrB acts as a positive regulator of PR and common clinical mutations lead to the addition of both L-Ara4N and pEtN to lipid-A, inducing notably higher polymyxin minimum inhibitory concentrations than mgrB disruption; a validated cause of PR. Additionally, crrB mutations induce a significant bacterial virulence increase at a notable fitness cost; partially from the activation of the pentose phosphate pathway. Our data demonstrate the importance of CrrB in high-level PR and establish important differences across CrrB alleles in balancing resistance with fitness and virulence.

Keywords: Antimicrobial Resistance, Klebsiella pneumoniae, Polymyxin, CrrB, Virulence, CRISPR Cas editing

Suggested Citation

McConville, Thomas Howe and Annavajhala, Medini K. and Giddins, Marla J. and Macesic, Nenad and Herrera, Carmen M. and Rozenberg, Felix D. and Bhushan, Gitanjali L. and Ahn, Danielle and Mancia, Filippo and Trent, Michael and Uhlemann, Anne-Catrin, CrrB Positively Regulates High-Level Polymyxin-Resistance and Virulence in Klebsiella pneumoniae. Available at SSRN: https://ssrn.com/abstract=3634809 or http://dx.doi.org/10.2139/ssrn.3634809
This version of the paper has not been formally peer reviewed.

Thomas Howe McConville

Columbia University - Division of Infectious Diseases ( email )

United States

Medini K. Annavajhala

Columbia University - Department of Medicine ( email )

United States

Marla J. Giddins

Columbia University - Division of Infectious Diseases ( email )

United States

Nenad Macesic

Monash University - Department of Infectious Diseases

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Carmen M. Herrera

Departments of Infectious Diseases, College of Veterinary Medicine, University of Georgia

Felix D. Rozenberg

Columbia University - Division of Infectious Diseases ( email )

United States

Gitanjali L. Bhushan

Columbia University - Division of Pediatric Critical Care ( email )

3022 Broadway
New York, NY 10027
United States

Danielle Ahn

Columbia University - Department of Pediatrics ( email )

NY
United States

Filippo Mancia

Columbia University - Department of Physiology ( email )

1150 St. Nicholas Ave., Room 508
Russ Berrie Pavilion
New York, NY 10032
United States

Michael Trent

University of Georgia - Department of Infectious Diseases

Anne-Catrin Uhlemann (Contact Author)

Columbia University - Department of Medicine

United States

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