Fig. 1
Molecular model of colistin binding to lipid A. a Schematic of phosphoethanolamine transfer to the 1-PO4 group of hexa-acylated lipid A as catalysed by MCR-1. b Models of colistin (blue sticks) binding to lipid A (left) or phosphoethanolamine-lipid A (right) (spheres coloured green, red, blue and orange for C, O, N and P atoms, respectively). The model is based on the NMR and docking studies of polymixin B binding to lipid A with lipid A coordinates from PDB 3fxi22 and colistin coordinates adapted from the NMR structure of polymixin B bound to lipid A23. The positively charged Dab colistin residues closely interact with the negatively-charged 1′ and 4′ phosphate groups of lipid A, reducing the net-negative charge of lipid A. The hydrophobic leucine residues and tail of colistin A interact with the fatty acid tails of lipid A, allowing colistin A to insert into, and disrupt, the bacterial outer membrane. b (right), model of colistin binding to phosphoethanolamine-lipid A indicates addition of positively charged phosphoethanolamine onto the 1′-PO4 of lipid A likely interferes with the interaction of positively charged Dab8 and Dab9 side chains with the phosphate group, preventing colistin binding to the outer membrane of Gram-negative bacteria. Figure created using Pymol (https://www.pymol.org/)
