An investigation on in vitro bacterial cell permeabilization of a ZnII-Curcumin complex along with exploration of the possibility of FtsZ inhibition by in silico simulation.

Curcumin is a multifaceted natural molecule having vast pharmacological potential. However, its translation from clinical trials is hindered by poor aqueous solubility and hydrolytic instability. To address these limitations and develop curcumin based antibacterial drugs, a ZnII-curcumin coordination compound was synthesized and evaluated for enhanced stability and antibacterial efficacy. Through an integrated approach of molecular docking-dynamics and biological assays, the mechanism behind effective antibacterial efficacy of ZnII-curcumin over curcumin was elucidated. Calcein leakage assay highlights ZnII-curcumin triggers significant membrane permeabilization corroborated by scanning and transmission electron microscopy. Studies show greater efficacy on Gram-positive bacteria S. aureus over Gram negative E. coli attributed to the presence of an outer membrane in Gram-negative bacteria. In silico analysis (molecular docking and 100 ns molecular dynamics) using two suitable protein models that identifies with FtsZ, a protein essential for bacterial cytokinesis was used as target. ZnII-curcumin was predicted to bind to FtsZ active site with much higher affinity than free curcumin; almost comparable to the model's native co-ligands. This computational prediction motivates but isn't necessarily a substitute for direct biochemical validation that we intend showing through some future work. The compound does not have adverse effects on mammalian cells, exhibiting a safe toxicological profile. Significance of this study lies in synthesizing a stable, metal-coordinated curcumin derivative that might operate in "dual target mode". By simultaneously disrupting membrane integrity and having the potential to inhibit cell division machinery, ZnII-curcumin provides a robust strategy to minimize risk of developing resistance. Overall, findings present ZnII-curcumin as a promising non-toxic candidate for therapeutic development to combat global crisis related to the development of resistance.