Abstract
MCR-1 is a phosphoethanolamine (pEtN) transferase that modifies the pEtN moiety of lipid A, conferring resistance to colistin, which is an antibiotic belonging to the class of polypeptide antibiotics known as polymyxins and is the last-line antibiotic used to treat multidrug resistant bacterial infections. Here we determined the crystal structure of the catalytic domain of MCR-1 (MCR-1-ED), which is originated in Escherichia coli (E. coli). MCR-1-ED was found to comprise several classical β-α-β-α motifs that constitute a “sandwich” conformation. Two interlaced molecules with different phosphorylation status of the residue T285 could give rise to two functional statuses of MCR-1 depending on the physiological conditions. MCR-1, like other known pEtN transferases, possesses an enzymatic site equipped with zinc binding residues. Interestingly, two zinc ions were found to mediate intermolecular interactions between MCR-1-ED molecules in one asymmetric unit and hence concatenation of MCR-1, allowing the protein to be oligomer. Findings of this work shall provide important insight into development of effective and clinically useful inhibitors of MCR-1 or structurally similar enzymes.
Highlights
MCR-1 is a phosphoethanolamine transferase that modifies the pEtN moiety of lipid A, conferring resistance to colistin, which is an antibiotic belonging to the class of polypeptide antibiotics known as polymyxins and is the last-line antibiotic used to treat multidrug resistant bacterial infections
We aimed at determining the structure of the extracellular domain of MCR-1, namely MCR-1-ED, which comprises residues 200~540 based on the sequence alignment between MCR-1 and LptA (PDB code: 4KAY) (Supplementary Fig. 3)
The two interlaced molecules are almost identical in their overall shape except at the potential catalytic sites T285 is phosphorylated in chain A but not in chain B (Fig. 1D) shown in omit density map as well (Supplementary Fig. 4), the structural details of which will be elaborated below
Summary
MCR-1 is a phosphoethanolamine (pEtN) transferase that modifies the pEtN moiety of lipid A, conferring resistance to colistin, which is an antibiotic belonging to the class of polypeptide antibiotics known as polymyxins and is the last-line antibiotic used to treat multidrug resistant bacterial infections. Since its discovery in November 2015, the mcr-1 gene has been reported in a wide range of bacterial species worldwide, suggesting that this resistance element is highly transmissible, posing a huge challenge to the use of polymyxin as a reserved drug for treatment of infections caused by CRE5. Development of effective inhibitors for MCR-1 may be the only effective strategy to prolong the use of colistin as the last-line antibiotic to treat life-threatening bacterial infections. For the first time, the crystal structure of MCR-1 in order to provide insight into both the structure/function relationship of this novel enzyme and facilitate development of countermeasures to reverse the colistin resistance phenotypes in major bacterial pathogens
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