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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.

ORGANISM(S): Klebsiella pneumoniae

PROVIDER: GSE307523 | GEO | 2025/09/16

REPOSITORIES: GEO

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Project description:Pseudomonas aeruginosa is a major opportunistic pathogen causing a wide range of infections and one of the most problematic bacteria regarding antibiotic resistance, with an increasing incidence of multidrug and extensively-drug resistant strains, including resistance to last resource antibiotics such as carbapenems. Resistances are often due to complex interplays of naturally and acquired resistance mechanisms which are enhanced by its remarkably large regulatory network. Thus, the use of non-targeted shotgun methodologies such as mass spectrometry-based proteomics is crucial to understand these interplays and to reveal possible strain and species-specific novel mechanisms of antibiotic resistance. The aim of this study was to determine the proteomic response of two carbapenem-resistant and extensively-drug-resistant P. aeruginosa strains to subminimal inhibitory concentrations (sub-MICs) of meropenem. The strains belonged to high-risk clones ST235 and ST395, one carrying a class 1 integron-encoded VIM-4 metallo-β-lactamase and one carrying no acquired antibiotic resistance genes. Each strain was cultivated with three different sub-MICs of meropenem, and a quantitative shotgun proteomic approach was applied, using tandem mass tag (TMT) isobaric labeling followed by nano-liquid chromatography tandem-mass spectrometry, to determine significantly up- or down-regulated proteins and enriched groups of proteins and pathways. Cultivation of both strains with ½ and ¼ of the MIC, resulted in hundreds of differentially regulated proteins, including several β-lactamases, transport-related proteins (including multiple porins and efflux pumps), proteins associated with peptidoglycan metabolism and cell wall organization and dozens of regulatory proteins. Remarkably, all components of the H1 type VI secretion system were up-regulated in one of the strains. Enrichment analyses revealed that multiple metabolic pathways were affected. Additionally, numerous proteins of unknown function were also differentially-regulated in each strain. In conclusion, high subminimal-inhibitory concentrations of meropenem cause massive changes in the proteomes of carbapenem-resistant P. aeruginosa strains, involving a wide range of common and strain-specific mechanisms and proteins, many still uncharacterized which might potentially play a role in the susceptibility of P. aeruginosa to meropenem.

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O-antigen Loss Modulates Meropenem Resistance in Klebsiella pneumoniae Through Metabolic and Redox Reprogramming

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