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mechanism for the auranofin-based Zn/Au exchange in NDM-1 includes the early formation of the Au(I)-Au(I) system, superseded by oxidation yielding the Au(II)-Au(II) species bearing the highest resemblance to the X-ray structure.

 

Comments：

This effect is achieved through the inhibition of the NDM-1 beta-lactamase enzyme, which is accomplished by substituting gold for zinc in the enzyme's bimetallic core.

The researchers used density functional theory calculations to investigate the unusual tetrahedral coordination of the two ions resulting from this substitution. By testing different charge and multiplicity schemes and constraining the positions of coordinating residues, they were able to determine 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 results suggest that the most likely mechanism for the auranofin-based Zn/Au exchange in NDM-1 involves the early formation of the Au(I)-Au(I) system, which is then followed by oxidation to produce the Au(II)-Au(II) species that most closely resembles the X-ray structure. Overall, this research provides insight into the molecular mechanisms underlying the effectiveness of auranofin as an antimicrobial agent.

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Related Targets

Bacterial Thioredoxin Reductase