O-antigen loss modulates meropenem resistance in Klebsiella pneumoniae through metabolic and redox reprogramming.

Abstract

Carbapenems are last line β lactam antibiotics for multidrug-resistant Gram-negative infections, yet the adaptive routes by which Enterobacterales survive carbapenem stress remain incompletely understood. Here we show that prolonged subinhibitory meropenem exposure promotes O antigen loss in Klebsiella pneumoniae, predominantly via insertion sequence-mediated disruption of O-antigen biosynthesis genes, thereby enhancing carbapenem resistance. O-antigen deficiency is accompanied by envelope-associated redox remodeling and reprogramming of central metabolism, mitigating meropenem-induced reactive oxygen species (ROS) accumulation and oxidative killing. This adaptation also conferred collateral sensitivity to aminoglycosides, associated with increased outer-membrane electronegativity and altered porin expression that may promote aminoglycoside uptake. Analysis of public genomes further revealed O-antigen locus disruptions in subsets of K. pneumoniae and Escherichia coli isolates. Together, our findings establish O-antigen deficiency as a surface-remodeling adaptation that enhances carbapenem resistance through coordinated metabolic and redox reprogramming, while exposing an aminoglycoside vulnerability that warrants further evaluation.

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