Biosynthesis of fosfomycin-loaded CuO nanoparticles: evaluation of antibacterial, antibiofilm properties and molecular docking analysis against biofilm-associated proteins in MDR bacteria.

BACKGROUND: Infectious diseases caused by antibiotic-resistant bacteria pose a significant challenge in healthcare. The development of new antibiotics, while essential, is often hindered by the complexity, cost, and time involved in the process. An alternative approach gaining traction is the conjugation of existing antibiotics with potent antimicrobial agents to improve their efficacy against resistant pathogens.

OBJECTIVE: This study aimed to develop environmentally sustainable and cost-effective copper oxide nanoparticles (CuO NPs) synthesized using bioactive compounds extracted from Curcuma zedoaria.

METHODS: These nanoparticles were subsequently conjugated with fosfomycin. Physicochemical characterization was carried out using XRD, scanning electron microscopy (SEM), FTIR, and UV-Visible spectroscopy. Release was studied using Franz diffusion cell. Antibacterial efficacy of the pure and fosfomycin-conjugated copper oxide nanoparticles (Fos-CuO NPs) was evaluated against multidrug-resistant (MDR) strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa using the disk diffusion method. The minimum inhibitory concentration (MIC) and antibiofilm activity were determined using the microbroth dilution method. Additionally, molecular docking analysis was performed to examine the interaction of Fos-CuO NPs with biofilm-associated proteins (LecA, CdrA, PslA, PslD, GacA, CupA, DipA, PelA, PelB) in P. aeruginosa.

RESULTS: The physicochemical analysis confirmed successful CuO NPs synthesis and their conjugation with fosfomycin. XRD results confirmed the crystalline structure of the nanoparticles, while SEM revealed some agglomerated, irregular spherical shapes. Fos-CuO NPs exhibited greater antibacterial activity against MDR S. aureus (42 mm), E. coli (45 mm), and P. aeruginosa (39 mm) compared with pure CuO NPs (39 mm, 27 mm, and 41 mm, respectively). The docking results showed that the fosfomycin-conjugated nanoparticle exhibited the highest binding affinity for the biofilm-associated proteins Lec A and Pel A, with docking scores of -4.4 kcal/mol and -4.9 kcal/mol, respectively, compared with blank CuO NPs, supporting their potential application as a novel antimicrobial strategy.

CONCLUSION: This research offers significant insights into the green synthesis of fosfomycin-conjugated nanoparticles for addressing the growing challenge of multidrug-resistant bacterial infections.