In Escherichia coli, transient resistance to polymyxin B can be conferred via modifications of lipopolysaccharide (LPS). The signal transduction events leading to LPS modification are coordinated by two interacting two-component systems, QseBC and PmrAB. Activation of the PmrB histidine kinase by one of its ligands – ferric iron – leads to phosphorylation of the cognate partner PmrA and non-cognate QseB, which together mediate the response. Deletion of either qseB or pmrA drastically reduces polymyxin B resistance, while deletion of both phenocopies the pmrB-deletion phenotype, yielding a strain that is unable to survive polymyxin B assault. While the targets of PmrA have been elucidated in detail and comprise several enzymes involved in lipid A modification, the role of QseB in coordinating the response to polymyxin B is elusive. We will discuss evidence that QseB coordinates the metabolic response that provides acetyl-CoA for LPS precursor synthesis. A combination of chIP-on-chip and RNAseq analyses elucidated that – among other targets – activated QseB controls expression of asnB, panD and coaA that encode key enzymes in the coenzyme A biosynthesis. Consistent with these observations, aspartate and acetyl-coA concentrations increase in a QseB-dependent manner, in strains challenged with polymyxin B. Deletion of qseB abrogates these metabolic changes. The results thus provide a new model in which QseB coordinates the metabolic shift to allow for LPS modification by the enzymes regulated by PmrA.