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O-antigen Deficiency Sparks Metabolic Shifts That Blunt ROS-Mediated Killing by Meropenem

ABSTRACT: Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a major global health threat, particularly in healthcare-associated infections. While carbapenemase- and porin-centered mechanisms are well characterized, how subinhibitory carbapenem exposure selects noncanonical adaptive routes remains unclear. Here, we show that subinhibitory meropenem promotes O_x001E_antigen loss in K. pneumoniae, predominantly mediated by insertion sequences (IS), thereby enhancing carbapenem resistance. O_x001E_antigen deficiency rewires metabolism under meropenem pressure, especially glycine, serine, and threonine pathways, dampening reactive oxygen species (ROS) accumulation and limiting oxidative killing; exogenous glycine restores ROS production and meropenem susceptibility. Genomic surveys reveal widespread O_x001E_antigen loss in K. pneumoniae, largely driven by IS, and also in Escherichia coli, and O_x001E_antigen–deficient mutants confirm its role in promoting carbapenem resistance. Importantly, this adaptation entails a trade-off: it improves survival under carbapenem pressure but increases serum susceptibility, destabilizes the capsule, attenuates virulence in murine infection models, and confers collateral sensitivity to aminoglycosides. These findings uncover a previously unrecognized route to carbapenem resistance that links O_x001E_antigen remodeling to metabolic rewiring, offering conceptual and therapeutic leverage points.

ORGANISM(S): Klebsiella pneumoniae

PROVIDER: GSE307523 | GEO | 2025/09/16

REPOSITORIES: GEO

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O-antigen Deficiency Sparks Metabolic Shifts That Blunt ROS-Mediated Killing by Meropenem

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