Abstract
Plasmid-mediated colistin resistance (mcr) determinants are challenging the efficacy of polymyxins against Gram-negative pathogens. Among 10 mcr genes described so far, the major determinants mcr-1 and mcr-3 are found closely linked to hpap2 or dgkA genes, encoding a hypothetical phosphatidic acid phosphatase of type 2 (PAP2) and a diacylglycerol kinase, respectively, whose functions are still unknown. In this study, mcr-1, mcr-1–hpap2, mcr-3, and mcr-3–dgkA were expressed in Escherichia coli, and recombinant strains were analyzed to detect antimicrobial susceptibility and changes in the expression of genes involved in phospholipid metabolism. The mcr-1 or mcr-3 single genes were enough to drive growth on colistin selective media, although co-expression of linked genes conferred maximal antibiotic resistance. Expression of mcr determinants downregulated endogenous genes involved in lipopolysaccharide (LPS) modification or phospholipid recycling, although to different extents of repression: strong for arnB, ybjG, and pmrR; medium for eptA, lpxT, and dgkA; small for bacA and pgpB. Four of these genes (bacA, lpxT, pgpB, and ybjG) encode undecaprenyl pyrophosphate (UPP) phosphatases. In these conditions, cells presented resistance against bacitracin, an antibiotic that sequesters UPP from PAP2 enzymes. The hpap2 and dgkA genes might play a role in colistin resistance by compensating for phospholipid metabolism functions altered during LPS modification by colistin resistance determinants.
Highlights
In the narrow frame of only four years, the wide spread of Enterobacteriaceae spp. resistant to polymyxins became a world-scale challenge to the efficacy of these compounds as last-resort antimicrobials [1]
This regulatory circuit could be lost by mutations in critical residues that produce the constitutive activation of PmrA or PmrB and, colistin resistance
The time-off for polymyxins ended with the detection of plasmid-mediated colistin-resistance determinants, carried by different plasmids that in many cases are transferred by conjugation with high efficiency and belonging to the same gene family but far related to eptA [1]
Summary
In the narrow frame of only four years, the wide spread of Enterobacteriaceae spp. resistant to polymyxins became a world-scale challenge to the efficacy of these compounds as last-resort antimicrobials [1]. PmrA regulates expression from the arnBCADTEF operon (pmrHFIJKLM) and ugd (pmrE) gene, encoding enzymes for synthesis and transfer of L-4-aminoarabinose (L-Ara4N) to the 40 -phosphate of lipid. Less interaction with external cations such as iron in turn decreases PmrAB activation, a negative feedback that balances excess LPS decoration [3]. This regulatory circuit could be lost by mutations in critical residues that produce the constitutive activation of PmrA or PmrB and, colistin resistance. The time-off for polymyxins ended with the detection of plasmid-mediated colistin-resistance determinants (mcr), carried by different plasmids that in many cases are transferred by conjugation with high efficiency and belonging to the same gene family but far related to eptA [1]
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