Multitargeting Antibacterial Activity of a Synthesized Mn²⁺ Complex of Curcumin on Gram-Positive and Gram-Negative Bacterial Strains

Abstract

Curcumin is an important molecule with a plethora of pharmacological activities and therapeutic potentials. Despite its efficacy, it remained a potential drug candidate owing to hydrolytic instability and poor aqueous solubility. To overcome the limitations related to low solubility, low bioavailability, and the fact that curcumin is never present in solution as a “single unit”, its complex was prepared with Mn II with the idea that binding to a metal ion might help to resolve these issues. The complex was characterized by elemental and spectral analysis. The structure of the complex was determined by density functional theory calculations. The complex was stable at physiological buffer conditions, unlike curcumin. It did not have any detrimental effect on mammalian cells. There was a significant enhancement in the antibacterial activity of the complex compared to curcumin against both Gram-positive ( Staphylococcus aureus ) and Gram-negative ( Escherichia coli ) bacteria. It showed a strong affinity for deoxyribonucleic acid (DNA) evident from a high binding constant value with calf thymus DNA and also from the retarded electrophoretic mobility of bacterial plasmid DNA. The complex showed “superoxide dismutase-like” activity leading to the generation of reactive oxygen species (ROS). The complex caused bacterial membrane perturbation evident from calcein leakage assay, which was further corroborated by scanning and transmission electron microscopic experiments. Overall, the present study shows improved stability and antibacterial potency of a nontoxic complex over curcumin. Its multitargeting mode of action such as ROS-production, effective binding with DNA, and permeabilization of bacterial membrane together allows it to be an effective antibacterial agent that could be taken further for therapeutic use against bacterial infections.

Free radical induced activity of an anthracycline analogue and its MnII complex on biological targets through in situ electrochemical generation of semiquinone

“…Since biological targets were present in the immediate vicinity of in situ electrochemically generated quinone-dianion or semiquinone they get an opportunity to interact with reduced species. In aerated medium, there is a possibility for the formation of superoxide radical anion and that here the Mn II complex could show SOD activity [ 53 ]. The time for in situ electrochemical generation of species was kept a constant so that similar charge was made available to each compound in all the sets of the experiment and that there is similar experimental error associated with the stimuli (here, the potentiostat) that helps to generate the reactive species.…”

“…Since Mn II complexes show significant SOD like activity and because Mn II is able to acquire higher oxidation states in presence of peroxides that are generated as part of ROS, we wanted to see if the Mn II complex would be beneficial for cell killing [ 52 , 53 ]. It is reported that almost all mitochondria contain a form of Mn-SOD where Mn could be in +2 or +3 oxidation states [ 54 ].…”

Metal–Curcumin Complexes in Therapeutics: An Approach to Enhance Pharmacological Effects of Curcumin

“…Zinc-curcumin Increases antioxidant enzymes and decreases MDA level caused by cold-restraint stress in mice [17] Iron-curcumin Improves antioxidant activity [18] Gold NP-curcumin Shows good antioxidant activity [19] Silver-curcumin Presents good antioxidant activity and cell compatibility [20] Copper-curcumin Zinc-curcumin Enhances the superoxide dismutase, catalase, and glutathione peroxidase activities and attenuates MDA levels in PC12 cells [21] Copper-curcumin Exhibits antioxidant potential by scavenging DPPH radicals [11] Zinc NP-curcumin Exerts antioxidant activity as it scavenges ABTS+ and DPPH free radicals [22] Ruthenium-curcumin Exhibits potent antioxidant activity [23] Gallium-diacetylcurcumin Presents an increase in the antioxidant efficiency [24] Anti-inflammatory Zinc-curcumin Suppresses NF-κB, TGF-β1, IL-8, IL-6, TNF-α in rat model [25,26] Copper-curcumin Suppresses PKCδ and NF-κB [27] Zinc-curcumin Copper-curcumin Inhibits H 2 O 2 -induced NF-κB in PC12 cells [21] Gadolinium-curcumin Inhibits pIKKα, pIKKα/β, and NF-κB in pancreatic cancer cells [28] Anti-microbial Cobalt-, Nickel-, Copper-curcumin Inhibits growth of E. coli, S. aureus, K. pneumoniae, S. pyogenes, and P. aeruginosa [29] Zinc-curcumin Inhibits growth of P. aeruginosa [30] Zinc-curcumin Inhibits growth of B. subtilis, E. coli [22] Ruthenium-curcumin Inhibits growth of drug resistant S. aureus, reduces mean bacterial counts in murine model of Staphylococcus infection [31,32] Manganese-curcumin Inhibits growth of S. aureus, E. coli [32] Silver-curcumin Combats multiple bacteria-induced infections on wound surfaces [20] Copper-curcumin Exhibits antimicrobicidal activity [33] Copper-curcumin Inhibits growth of P. aeruginosa [34] Orthovanadium-curcumin Inhibits bacterial biofilm formation, growth of S. aureus and E. coli [35] Copper-curcumin Inhibits growth of P. aeruginosa and biofilm formation [34] Ruthenium-curcumin Exhibits strong antibiofilm activity [31] Zinc-curcumin Exerts potency against biofilm formation [30]…”

“…The Mn 2+ -curcumin complex has been shown to possess significant antibacterial activity against both Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria compared to free curcumin [32]. Another curcumin complex with rare earth metal (rare earth(III) nitrate) also exhibited strong antibacterial activity compared to that of curcumin alone [50].…”

“…A Mn 2+ -curcumin complex was also synthesized to determine the hydrolytic stability of the complex. It was found that the Mn 2+ -curcumin complex is stable in physiological buffers and media, as opposed to curcumin, even under reducing conditions [32]. The gallium complexed curcumin increases the stability, cellular uptake, and bioavailability of curcumin in both in vitro and in vivo cancer models [110].…”