Over the past years, multiresistant bacteria have gained more and more ground, leaving once very effective antibacterial drugs without effect over certain bacteria. Thus, the scientific community is in search for new active compounds, e.g. new derivatives of antibiotics like penicilline or complexes with precious or essential metal ions, known since antiquity for their antimicrobial properties.[1] Even the ancient Greeks and Romans used silver vessels to keep the liquids fresh or ate from silver plates, which developed into the tradition to throw a silver coin into a fountain.[2] Today, more is known about the antimicrobial effect of silver. It has for example been found that silver ions (Ag⁺) damage the DNA of bacteria by interfering with guanine and adenine base pairs[3] and that they induce an overproduction of reactive oxygen species (ROS) such as hydroxyl radicals by disrupting the metabolic pathways of Fenton chemistry.[4–5] Moreover, it is known that silver ions interact strongly with thiol groups and inhibit or degrade therefore the disulfide bond formation in many proteins and enzymes and that they increase the bacterial membrane permeability.[4] Based on our extensive experience with antimicrobial silver compounds[6–8] and silver resistance of bacteria[5,9], we now present combinations of silver ions with the alike antibacterial and immunologically active metal ion zinc (Zn²⁺)and the antibacterial and angiogenic active metal ion copper (Cu²⁺) in mixed-metal complexes with the bioinspired ligand L-p-aminophenylalanine (L-papa). The hypothesis hereby is to create a synergistic antimicrobial effect of two antimicrobial metal ions in order to fight more efficiently against bacteria.

The interaction between the metal ions and the ligand L-papa has been widely explored by solution (ESI-MS, ¹H-NMR) and solid studies (P-XRD, SC-XRD, FT-IR, DSC etc.) and gives us evidence for the stability of the complexes and the release of the bioactive metal ions. Recent results of the antimicrobial essays showed inhibition and/or bactericidal effect at certain concentrations of the different complexes against gram-negative bacteria Escherichia coli and gram-positive bacteria Staphylococcus aureus. Exact studies for the determination of minimal inhibitory and bactericidal concentration (MIC and MBC) as well as the corresponding biocompatibility essays with mouse embryonic fibroblasts are currently ongoing and promising for bimetallic complexes.

Moreover, other ligands like L-histidine (important for the immune system[10]) and L-carnosine (a promising wound healing agent[11]) in terms of the complexation with the above-mentioned metal ions are being studied. Crystallization essays in different solvents and concentrations are being carried out to obtain the structure of the new compounds. Such complexes will be incorporated into bioscaffolds made by electrospinning. This new class of antimicrobial biohybrid-nanofibers are investigated regarding medical applications in wound dressings or on implants as well as in vascular tissue engineering with a variety of physical and biological techniques.

[1]   Marin, E., Boschetto, F., Pezzotti, G. j- Biomed. Mater. Res. 2020, 108, 1617–1633.
[2]   K. M. Fromm, Nat Chem 2011, 3.
[3]   H. Arakawa, J. F. Neault, H. A. Tajmir-Riahi, Biophysical Journal 2001, 81, 1580-1587.
[4]   J. R. Morones-Ramirez, J. A. Winkler, C. S. Spina, J. J. Collins, Science Translational Medicine 2013, 5, 190ra181-190ra181.
[5]   S. Eckhardt, P. S. Brunetto, J. Gagnon, M. Priebe, B. Giese, K. M. Fromm, Chem Rev 2013, 113, 4708-4754.
[6]   M. Varisco, N. Khanna, P. S. Brunetto, K. M. Fromm, ChemMedChem 2014, 9, 1221-1230.
[7]   I. Chevrier, J. L. Sague, P. S. Brunetto, N. Khanna, Z. Rajacic, K. M. Fromm, Dalton Trans 2013, 42, 217-231.
[8]   M. Claudel, J. V. Schwarte, K. M. Fromm; Chemistry 2020, 2(4), 849–899.
[9]   L. Mirolo, T. Schmidt, S. Eckhardt, M. Meuwly, K. M. Fromm, Chem. Eur. J. 2013, 19, 1754–1761.
[10] Holeček, Milan Nutrients 2020, 12, 848.
[11] Ansurudeen, I., Sunkari, V.G., Grünler, J. et al. Amino Acids 2012, 43, 127–134.