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Plasmid-mediated colistin resistance (<i>mcr</i>) determinants are challenging the efficacy of polymyxins against Gram-negative pathogens. Among 10 <i>mcr</i> genes described so far, the major determinants <i>mcr-1</i> and <i>mcr-3</i> are found closely linked to <i>hpap2</i> or <i>dgkA</i> genes, encoding a hypothetical phosphatidic acid phosphatase of type 2 (PAP2) and a diacylglycerol kinase, respectively, whose functions are still unknown. In this study, <i>mcr-1</i>, <i>mcr-1–hpap2</i>, <i>mcr-3</i>, and <i>mcr-3–dgkA</i> were expressed in <i>Escherichia coli</i>, and recombinant strains were analyzed to detect antimicrobial susceptibility and changes in the expression of genes involved in phospholipid metabolism. The <i>mcr-1</i> or <i>mcr-3</i> single genes were enough to drive growth on colistin selective media, although co-expression of linked genes conferred maximal antibiotic resistance. Expression of <i>mcr</i> determinants downregulated endogenous genes involved in lipopolysaccharide (LPS) modification or phospholipid recycling, although to different extents of repression: strong for <i>arnB</i>, <i>ybjG</i>, and <i>pmrR</i>; medium for <i>eptA</i>, <i>lpxT</i>, and <i>dgkA</i>; small for <i>bacA</i> and <i>pgpB.</i> Four of these genes (<i>bacA</i>, <i>lpxT</i>, <i>pgpB</i>, and <i>ybjG</i>) encode undecaprenyl pyrophosphate (UPP) phosphatases. In these conditions, cells presented resistance against bacitracin, an antibiotic that sequesters UPP from PAP2 enzymes. The <i>hpap2</i> and <i>dgkA</i> genes might play a role in colistin resistance by compensating for phospholipid metabolism functions altered during LPS modification by colistin resistance determinants.