Auranofin Targeting the NDM-1 Beta-Lactamase: Computational Insights into the Electronic Configuration and Quasi-Tetrahedral Coordination of Gold Ions

Recently, the well-characterized metallodrug auranofin has been demonstrated to restore the penicillin and cephalosporin sensitivity in resistant bacterial strains via the inhibition of the NDM-1 beta-lactamase, which is operated via the Zn/Au substitution in its bimetallic core. The resulting unusual tetrahedral coordination of the two ions was investigated via the density functional theory calculations. By assessing several charge and multiplicity schemes, coupled with on/off constraining the positions of the coordinating residues, it was demonstrated that the experimental X-ray structure of the gold-bound NDM-1 is consistent with either Au(I)-Au(I) or Au(II)-Au(II) bimetallic moieties. The presented results suggest that the most probable mechanism for the auranofin-based Zn/Au exchange in NDM-1 includes the early formation of the Au(I)-Au(I) system, superseded by oxidation yielding the Au(II)-Au(II) species bearing the highest resemblance to the X-ray structure.