Studies of viomycin, an anti-tuberculosis antibiotic: Copper(II) coordination, DNA degradation and the impact on delta ribozyme cleavage activity

Viomycin is a basic peptide antibiotic, which is among the most effective agents against multidrug-resistant tuberculosis. In this paper we provide the characteristics of its acid base properties, coordination preferences towards the Cu(II) ions, as well as the reactivity of the resulting complexes against plasmid DNA and HDV ribozyme. Careful coordination studies throughout the wide pH range allow for the characterisation of all the Cu(II)-viomycin complex species. The assignment of proton chemical shifts was achieved by NMR experiments, while the DTF level of theory was applied to support molecular structures of the studied complexes. The experiments with the plasmid DNA reveal that at the physiological levels of hydrogen peroxide the Cu(II)-viomycin complex is more aggressive against DNA than uncomplexed metal ions. Moreover, the degradation of DNA by viomycin can be carried out without the presence of transition metal ions. In the studies of antigenomic delta ribozyme catalytic activity, viomycin and its complex are shown to modulate the ribozyme functioning. The molecular modelling approach allows the indication of two different locations of viomycin binding sites to the ribozyme

Capreomycin - A polypeptide antitubercular antibiotic with unusual binding properties toward copper(II)

Capreomycin is an important therapeutic agent having intriguing and diverse molecular features. Its polypeptidic structure rich in nitrogen donors makes the drug a promising chelating agent for a number of transition metal ions, especially for copper(II). The results of the model investigational studies suggest that capreomycin anchors Cu(2+) ion with an amino function of the alpha,beta-diaminopropionic acid residue at pH around 5. At physiological pH copper(II) ion is coordinated by two deprotonated amide nitrogen atoms of the alpha,beta-diaminopropionic acid, the serine residue as well as the amino function deriving from the beta-lysine. Above that pH value we observe a rearrangement within the coordination sphere leading to movement of Cu(2+) to the center of the peptide ring with concurrent coordination of four nitrogen donors. Spin-lattice relaxation enhancements and potentiometric measurements clearly indicate that deprotonated amide nitrogen atom from the beta-ureidodehydroalanine moiety is the fourth donor atom

Identification of copper(II) binding sites in the aminoglycosidic antibiotic Neomycin B

Protonation and copper(II) coordination properties of neomycin B were studied in solution by potentiometry, NMR, UV/Vis, CD, and EPR spectroscopy, XAS and mass spectrometry. Mono- and dinuclear complexes were found depending on the metal-to-ligand molar ratio. Neomycin B anchors CuII ions above pH 5.0 with an NH2 group from ring B. Simultaneously, the second amino group of the same ring and the hydroxyl group of ring A complete the binding set of donors. With an increase in pH the remaining –NH3+ functional groups in the neomycin B molecule are deprotonated without affecting the complexation pattern. However, these groups, particularly the ones located in the D-ring of the antibiotic, may coordinate the second copper(II) ion when the metal is present in excess. We have proved this process with the use of potentiometry, CD and especially mass spectrometry

Cu(II) ion interaction with teicoplanin-vancomycin's analog

Teicoplanin, a member of the ‘‘last chance” antibiotic family has a similar structure and the same mechanism of action as parent drug vancomycin, which is proved to be an effective binder of Cu(II) ions. However, the potentiometric and spectroscopic studies (UV–visible, CD, NMR) have shown that the modification of the N-terminal structure of the peptide backbone in teicoplanin affects considerably the binding ability towards Cu(II) ions. While vancomycin forms almost instantly the stable 3 N complex species involving the N-terminal and two amide nitrogen donors, in case of teicoplanin only two nitrogen donors derived from the N-terminal amino group and adjacent peptide bond are coordinated to Cu(II) ion within the whole pH range studied. The major factor influencing the binding mode is most likely the structure of the N-terminus of the peptide unit in the antibiotic ligand

NMR and EPR Structural Delineation of Copper(II) Complexes Formed by Kanamycin A in Water.

The complexes formed by kanamycin A at three different pH values (5.5, 7.4 and 12.0) were investigated by NMR and EPR spectroscopy. The interaction of the Cu(II) ion with the nitrogen of the C ring is apparent at all pH values. At higher pH also the amino group of ring A starts to be involved in the metal coordination sphere. This is accompanied by a switch in conformation of ring C. Structures are consistent with the involvement in the coordination sphere either of the 2 or 4 hydroxyl oxygens at pH 5.5 and the 5 and the 6 hydroxyl oxygens (or the ring oxygen) at pH 12.0

Impact of Cu2+ ions on the structure of colistin and cell-free system nucleic acid degradation

Colistin and transition metal ions are commonly used as feed additives for livestock animals. This work presents the results of an analysis of combined potentiometric and spectroscopic (UV-vis, EPR, CD, NMR) data which lead to conclude that colistin is able to effectively chelate copper(II) ions. In cell-free system the oxidative activity of the complex manifests itself in the plasmid DNA destruction with simultaneous generation of reactive (OH)-O-center dot species, when accompanied by hydrogen peroxide or ascorbic acid. The degradation of RNA occurs most likely via a hydrolytic mechanism not only for complexed compound but also colistin alone. Therefore, huge amounts of the used antibiotic for nontherapeutic purposes might have a potential influence on livestock health. (C) 2015 Elsevier Inc. All rights reserved

Stability and Structure of Mixed Ligand Metal Ion Complexes Containing Ni2+, Cu2+ or Zn2+, and Histamine as well as Adenosine 5'-Triphosphate (ATP4–) or Uridine 5'-Triphosphate (UTP4–) : an Intricate Network of Equilibria

With a view on protein–nucleic acid interactions in the presence of metal ions we studied the “simple” mixed-ligand model systems containing histamine (Ha), the metal ions Ni2+, Cu2+, or Zn2+ (M2+), and the nucleotides adenosine 5′-triphosphate (ATP4−) or uridine 5′-triphosphate (UTP4−), which will both be referred to as nucleoside 5′-triphosphate (NTP4−) . The stability constants of the ternary M(NTP)(Ha)2− complexes were determined in aqueous solution by potentiometric pH titrations. We show for both ternary-complex types, M(ATP)(Ha)2− and M(UTP)(Ha)2−, that intramolecular stacking between the nucleobase and the imidazole residue occurs and that the stacking intensity is approximately the same for a given M2+ in both types of complexes: The formation degree of the intramolecular stacks is estimated to be 20 to 50 %. Consequently, in protein–nucleic acid interactions imidazole–nucleobase stacks may well be of relevance. Furthermore, the well-known formation of macrochelates in binary M2+ complexes of purine nucleotides, that is, the phosphate-coordinated M2+ interacts with N7, is confirmed for the M(ATP)2− complexes. It is concluded that upon formation of the mixed-ligand complexes the M2+N7 bond is broken and the energy needed for this process corresponds to the stability differences determined for the M(UTP)(Ha)2− and M(ATP)(Ha)2− complexes. It is, therefore, possible to calculate from these stability differences of the ternary complexes the formation degrees of the binary macrochelates: The closed forms amount to (65±10) %, (75±8) %, and (31±14) % for Ni(ATP)2−, Cu(ATP)2−, and Zn(ATP)2−, respectively, and these percentages agree excellently with previous results obtained by different methods, confirming thus the internal validity of the data and the arguments used in the evaluation processes. Based on the overall results it is suggested that M(ATP)2− species, when bound to an enzyme, may exist in a closed macrochelated form only, if no enzyme groups coordinate directly to the metal ion