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.
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