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Antibiotic resistance is a global healthcare crisis. Bacteria are highly adaptable and can rapidly acquiremechanisms of resistance towards conventional antibiotics. The permeability barrier conferred by theGram-negative bacteria cell envelope constitutes a first line of defence against the action ofantibiotics. Exposure to extracytoplasmic stresses can negatively affect cell envelope homoeostasisand this causes localised protein misfolding, compromised envelope integrity and impairs barrierfunction. The CpxA-CpxR two-component regulatory system has evolved to sense extracytoplasmicstresses and to regulate processes that restore homoeostasis of the cell envelope. Hence, controlledCpx-signalling assists bacteria in adapting, surviving and proliferating in harsh environments,including exposure to antibiotics. Herein, we determined that an intact Cpx-signalling is key tomaintaining the Yersinia pseudotuberculosis resistance to colistin and polymyxin B. The susceptibilitydisplayed by Cpx-signalling defective mutants, correlated with cell-envelope deformity and specificmodifications of Lipid-A. In vivo transcriptional analysis and in vitro protein-DNA binding studiesdemonstrated that these modifications were dependent on the direct regulation of Lipid-A biogenesisand modifications of operons by the active phosphorylated CpxR~P isoform. Altogether, our workdefines the regulatory mechanism that enables Cpx-signalling to actively control cell enveloperemodelling and the permeability of antibiotics in the clinically relevant enteropathogen Y.pseudotuberculosis.