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

Polymyxin resistance (PR) threatens the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. PR frequently arises through chemical modification of the lipid A portion of lipopolysaccharide. Various mutations are implicated in PR, including in three two-component systems—CrrA/B,...

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Detalles Bibliográficos
Autores principales: McConville, Thomas H., Annavajhala, Medini K., Giddins, Marla J., Macesic, Nenad, Herrera, Carmen M., Rozenberg, Felix D., Bhushan, Gitanjali L., Ahn, Danielle, Mancia, Filippo, Trent, M. Stephen, Uhlemann, Anne-Catrin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656232/
https://www.ncbi.nlm.nih.gov/pubmed/33113377
http://dx.doi.org/10.1016/j.celrep.2020.108313
Descripción
Sumario:Polymyxin resistance (PR) threatens the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. PR frequently arises through chemical modification of the lipid A portion of lipopolysaccharide. Various mutations are implicated in PR, including in three two-component systems—CrrA/B, PmrA/B, and PhoP/Q—and the negative regulator MgrB. Few have been functionally validated. Therefore, here we adapt a CRISPR-Cas9 system to CRKP to elucidate how mutations in clinical CRKP isolates induce PR. We demonstrate that CrrB is a positive regulator of PR, and common clinical mutations lead to the addition of both 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosophethanolamine (pEtN) to lipid A, inducing notably higher polymyxin minimum inhibitory concentrations than mgrB disruption. Additionally, crrB mutations cause a significant virulence increase at a fitness cost, partially from 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.