Multi-drug resistance is one of the major threats to public health. In our earlier research, we have identified several classes of compounds with a NNSN structural motif, which show copper-activation, a significant increase of toxicity against MRSA and other Gram-positive organisms in the presence of copper (I). The increased copper-concentration enables chelation by compounds with NNSN-motif within, thus enabling the effective targeting of infected cells. This strategy takes advantage of the fact that free copper(I) and (II) are virtually unavailable in mammalian bodies, except in activated phagosomes. There, cells use a “brass dagger” by increasing the concentration of copper(I) and zinc(II) while decreasing iron(II) and other nutrients. The beauty of this approach is that we can use “somatic intelligence” for very effective targeting of pathogens by administering essentially non-toxic compounds in relatively large concentrations and by assigning the job of pathogen-recognition to the cells. We have studied the mechanism of copper(I)-activation by means of <sup>1</sup>H-NMR titrations, UV/Vis-spectroscopic adsorption studies, calculation of adsorption isotherms, and computer-simulation (force-field). The implications of these studies for the design of structure-activity relationship studies of copper-activated compounds will be discussed.

Mechanistic studies of copper-activated drugs against Gram-positive bacteria

255th National Meeting (2018)

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