Antibacterial activity of Mn(i) and Re(i) tricarbonyl complexes conjugated to a bile acid carrier molecule

A bifunctional cholic acid–bis(2-pyridylmethyl)amine (bpa) ligand featuring an amide linker was coordinated to a manganese(I) or rhenium(I) tricarbonyl moiety to give [M(bpa^cholamide)(CO)3] with M = Mn, Re in good yield and very high purity. Strong antibacterial activity was observed against four strains of methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, with minimum inhibitory concentrations (MICs) in the range of 2–3.5 μM. No difference in response was observed for the MSSA vs. MRSA strains. Activity was also independent of the nature of the metal center, as the Mn and Re complexes showed essentially identical MIC values. In contrast to some other metal carbonyl complexes, the activity seems to be unrelated to the release of carbon monoxide, as photoactivation of the Mn complex reduced the potency by a factor of 2–8. Both metal complexes were non-toxic in Galleria mellonella larvae at concentrations of up to 100× the MIC value. In vivo testing in Galleria larvae infected with MRSA/MSSA demonstrated a significant increase in overall survival rates from 46% in the control to 88% in the group treated with the metal complexes. ICP-MS analysis showed that the Mn and Re cholamide complexes are efficiently internalized by E. coli cells and do not interfere with membrane integrity, as evident from a lack of release of intracellular ATP. An increased sensitivity was observed in acrB, acrD, and mdt mutants that are defective in multidrug exporters, indicating that the compounds have an intracellular mechanism of action. Furthermore, E. coli mntP mutants defective in the gene encoding an Mn exporter were more sensitive than the wildtype, while inactivation of the regulator that controls expression of the Mn uptake proteins MntP and MntH slightly increased sensitivity to the compound. Single knockout mutants defective in genes linked to bile salt and oxidative stress response (dinF, yiaH, sodA, katE, and soxS) did not show increased sensitivity relative to the wild type. Overall, neither the cholic acid moiety nor the metal-carbonyl fragment alone appear to be responsible for the biological activity observed and thus the search for the primary intracellular target continues

Continuous multiparametric monitoring of cell metabolism in response to transient overexpression of the sirtuin deacetylase SIRT3

The analysis and visualisation of research data in an environment which is most similar to living conditions belong to the most challenging claims of present scientific research endeavours. To date, the effect of protein function on cell metabolism is most commonly assessed from a series of end point analyses, which finally allows an approximate estimation on how a specific effect takes its course. In the study presented herein, we demonstrate how the combination of transient transfection and a biosensor chip system gives the opportunity to analyse the effect of a specific protein on cell metabolism in living cells through real-time monitoring of metabolically relevant parameters, such as oxygen consumption, acidification rate and cell adhesion. In addition, this method allows online monitoring of the time course of metabolic changes due to changes in expression levels of metabolic regulative proteins from the time of transfection to maximum overexpression. The methodology presented herein was assessed for the transient overexpression of the sirtuin deacetylase SIRT3, a mitochondrial key element in the regulation of energy metabolism, metabolic disease, cancer and ageing

Effects of chirality on the intracellular localization of binuclear ruthenium(II) polypyridyl complexes

Interest in binuclear ruthenium(II) polypyridyl complexes as luminescent cellular imaging agents and for biomedical applications is increasing rapidly. We have investigated the cellular localization, uptake, and biomolecular interactions of the pure enantiomers of two structural isomers of [μ-bipb(phen)4Ru2]4+ (bipb is bis(imidazo[4,5-f]-1,10-phenanthrolin-2-yl)benzene and phen is 1,10-phenanthroline) using confocal laser scanning microscopy, emission spectroscopy, and linear dichroism. Both complexes display distinct enantiomeric differences in the staining pattern of fixed cells, which are concluded to arise from chiral discrimination in the binding to intracellular components. Uptake of complexes in live cells is efficient and nontoxic at 5 μM, and occurs through an energy-dependent mechanism. No differences in uptake are observed between the structural isomers or the enantiomers, suggesting that the interactions triggering uptake are rather insensitive to structural variations. Altogether, these findings show that the complexes investigated are promising for future applications as cellular imaging probes. In addition, linear dichroism shows that the complexes exhibit DNA-condensing properties, making them interesting as potential gene delivery vectors

Small Signaling Molecules and CO-Releasing Molecules (CORMs) for the Modulation of the Cellular Redox Metabolism

Indeed, I firmly think that after the initial enthusiasm followed by a drawback experienced with redox-active therapeutics in humans, the field is now on a new and wide avenue of solid development, which is likely to become clinically successful ..

Release of Bioactive Molecules Using Metal Complexes

The biological activity of molecules is modulated by coordination to a transition metal centre. Ideally, this results in a completely inactive system, which acts as a prodrug, from which the bioactive component can be released by a specific trigger mechanism in a spatially and temporally controlled way. This chapter focuses on three different applications, to highlight general concepts as well as current challenges in the area: (1) the release of small-molecule messengers such as nitric oxide (NO) and carbon monoxide (CO) from the metal coordination sphere; (2) the "photouncaging" of organic neurotransmitters from metal complexes; and (3) the hypoxia-activated release of anticancer-active compounds from metal-based prodrugs

Synthesis, Structures, and CO Releasing Properties of two Tricarbonyl Manganese(I) Complexes

[MnBr(CO)5] reacts with one equivalent each of 1, 3, 5-triaza-7-phosphaadamantane (PTA) and sodium diethyldithiocarbamate to afford the yellow MnI complex fac-[Mn(S2CNEt2)(PTA)(CO)3]. Similarly, the same MnI precursor reacts with the sodium salt ofL-histidine to give the tricarbonyl manganese(I) complex fac-[Mn(his)(CO)3] in good yield as a yellow solid. Both compounds were spectroscopically and structurally characterised. The histidinato complex is soluble in water and its aqueous solutions are stable for more than 24 h. The CO releasing properties of the histidinato complex were studied with the myoglobin assay and establish this compound as a novel PhotoCORM, which liberates one of the three carbonyl ligands upon irradiation

Antibacterial and Antiparasitic Activity of Manganese(I) Tricarbonyl Complexes with Ketoconazole, Miconazole, and Clotrimazole Ligands

© 2015 American Chemical Society. Five manganese(I) tricarbonyl complexes of the general formula [Mn(CO)<inf>3</inf>(bpy<sup>R,R</sup>)(azole)]PF<inf>6</inf> with R = H, COOCH<inf>3</inf>, and azole = ketoconazole (ktz), miconazole (mcz), and clotrimazole (ctz) were synthesized and fully charaterized, including X-ray structure analysis for the ctz compound. The antibacterial activity on a panel of eight Gram-positive and Gram-negative bacterial strains was determined. While there was no effect on the latter microorganisms, the ctz complex showed submicromolar activity on Staphylococcus aureus and S. epidermidis with MIC values of 0.625 µM. Antiparasitic activity was investigated on Leishmania major and Trypanosoma brucei. Coordination of the organic azole drugs to the Mn(CO)<inf>3</inf> moiety led to complexes with low micromolar IC<inf>50</inf> values, but their potential for antileishmanial therapy is low due to comparable toxicity on mammalian cell lines 293T and J774.1. In contrast, the antitrypanosomal activity is much more promising, and the most potent compound incorparting the ktz ligand has an IC<inf>50</inf> value on T. brucei of 0.7 µM with selectivity on parasitic over mammalian cells as expressed by a selectivity index above 10. These results demonstrate that metal coordination of established drugs can significantly improve their biological activity and expand their range of medicinal applications. (Chemical Equation Presented)