Self-assembled gallic acid-rare earth nanocomplexes against MRSA with multi-targeting antibacterial mechanisms robustly combating bacterial resistance

Antibiotic resistance poses a significant threat to global public health, urgently demanding the development of new antibacterial agents with high efficacy and low resistance potential. In this study, we engineered self-assembled nanocomplexes of the gallic acid (GA) with rare earth (Re) ions (Ce 3+ , Gd 3+ , and Yb 3+ ), leveraging the unique multidentate structures of polyphenols to enhance antibacterial performance while minimizing resistance. These GA-Re nanocomplexes demonstrated potent activity against both antibiotic-sensitive Staphylococcus aureus (ASSA) and methicillin-resistant S. aureus (MRSA), with minimum inhibitory concentrations as low as 0.5 mmol/L. Viable MRSA cell numbers decreased from 7.40 × 10 7 CFU/mL to 8.43 × 10 6 and 7.33 × 10 2 CFU/mL when treated with penicillin (PEN) and GA-Gd for 24 h, respectively, indicating higher bactericidal efficiency of GA-Gd. Remarkably, no resistance developed in ASSA even after 60 days(d) of continuous exposure to GA-Gd, in contrast to the significant resistance observed with PEN (1024-fold) and neomycin (256-fold) after 28 d. The multidentate structure of GA facilitated versatile interactions with bacterial surface structures, enabling multiple mechanisms of action targeting cell walls, membranes, DNA, and cellular metabolism. Moreover, in vivo studies revealed that GA-Gd was effectively metabolized and excreted without accumulation or toxicity, and also accelerates the healing of MRSA infected wounds. These findings suggest the potential of self-assembled Re-based phenolic nanocomplexes as promising candidates for combating antibiotic-resistant bacterial infections, and pave the way for next-generation antibacterial agents.