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

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. Here, the authors show that prolonged subinhibitory meropenem exposure promotes O-antigen loss in Klebsiella pneumoniae and that this surface-remodeling adaptation enhances carbapenem resistance through coordinated metabolic and redox reprogramming.