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

• DOI: 10.1016/j.celrep.2020.108313
• Publication Date: 2020-10-27T14:36:54Z
• Authors: Thomas H. McConville; Medini K. Annavaj...; Marla J. Giddins; Nenad Macesic; Carmen M. Herrera; Felix D. Rozenberg; Gitanjali L. Bhushan; Danielle Ahn; Filippo Mancia; M. Stephen Trent; Anne-Catrin Uhlemann
• Keywords: Polymyxin; Lipid A; Polymyxin B

Polymyxin resistance (PR) threatens the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. PR frequently arises through chemical modification lipid A portion lipopolysaccharide. Various mutations are implicated in PR, including three two-component systems—CrrA/B, PmrA/B, and PhoP/Q—and negative regulator MgrB. Few have been functionally validated. Therefore, here we adapt a CRISPR-Cas9 system to CRKP elucidate how clinical isolates induce PR. We demonstrate that CrrB is positive common lead addition both 4-amino-4-deoxy-L-arabinose (L-Ara4N) phosophethanolamine (pEtN) A, inducing notably higher polymyxin minimum inhibitory concentrations than mgrB disruption. Additionally, crrB cause significant virulence increase at fitness cost, partially from activation pentose phosphate pathway. Our data importance high-level establish important differences across alleles balancing with virulence.