Synergistic antibacterial and biofilm eradication activity of quaternary-ammonium compound with copper ion

Antibiotics overuse and misuse increase the emergence of multidrug-resistant bacterial strains, which often leads to the failure of conventional antibiotic therapies. Even worse, the tendency of bacteria to form biofilms further increases the therapeutic difficulty, because the extracellular matrix prevents the penetration of antibiotics and triggers bacterial tolerance. Therefore, developing novel antibacterial agents or therapeutic strategies with diverse antibacterial mechanisms and destruction of bacteria biofilm is a promising way to combat bacterial infections. In the present study, the combination of quaternary ammonium compound poly(diallyl dimethyl ammonium chloride) (PDDA) with Cu2+ was screened out to fight common pathogenic Staphylococcus aureus (S. aureus) through multi-mechanisms. This combination appeared strong synergistic antibacterial activity, and the fractional inhibitory concentration index was as low as 0.032. The synergistic antibacterial mechanism involved the destruction of the membrane function, generation of intracellular reactive oxygen, and promotion more Cu2+ into the cytoplasm. Further, the combination of PDDA and Cu2+ reduced the extracellular poly-saccharide matrix, meanwhile killing the bacteria embedded in the biofilm. The biocompatibility study in vitro revealed this combination exhibited low cytotoxicity and hemolysis ratio even at 8 times of minimum bacteri-cidal concentration. This work provides a novel antibacterial agents combination with higher efficiency to fight planktonic and biofilm conditions of S. aureus.

Automated summary

Antibiotics overuse and misuse contribute to the emergence of multidrug-resistant bacterial strains and biofilm formation. This study screened out a combination of quaternary ammonium compound PDDA and Cu2+ as a promising antibacterial agent against Staphylococcus aureus. The combination showed strong synergistic antibacterial activity by disrupting membrane function, generating intracellular reactive oxygen, promoting Cu2+ uptake, and reducing biofilm extracellular matrix. In vitro biocompatibility studies demonstrated low cytotoxicity and hemolysis ratio. This work provides a novel and efficient strategy to combat planktonic and biofilm S. aureus infections.