Graphene oxide with acid-activated bacterial membrane anchoring for improving synergistic antibacterial performances

Abstract Bacterial resistance toward antibiotics has become a major threat to current anti-infective therapy, and now it's very urgent to develop new therapeutic drugs and coping strategies for overcoming bacterial resistance. Although graphene oxide (GO)-based nanocomposite has been widely used as antibacterial material, its antibacterial activity is still low and needs to be improved. Herein, we have presented a synergistic antibacterial agent, polyethyleneimine-citraconic anhydride modified and azithromycin-loaded GO nanosheet (AZI@GO-PEI-CA), which could selectively anchor bacterial membrane and improve antibacterial activity. The primary amine groups of polyethyleneimine (PEI) react with citraconic anhydride (CA), but could be recovered at acidic condition, which not only could increase its biocompatibility at physiological condition due to almost neutral charge of AZI@GO-PEI-CA after the introduction of CA, but also can enhance the anchoring of bacteria because AZI@GO-PEI-CA become highly positive after removal of CA under the acidic inflammatory microenvironment. Azithromycin (AZI) was conjugated onto GO due to that GO can not only physically insert the membrane of bacteria to kill bacteria but also help AZI enter the bacteria (such as Gram-positive S. aureus and Gram-negative E. coli), which could further inhibit ribosome biogenesis and protein synthesis. PEI-CA could increase anchor bacteria, GO and AZI could kill bacteria via different mechanism, therefore, the synergistic effect of PEI-CA, AZI, and GO in AZI@GO-PEI-CA nanoparticles could effectively kill bacteria. In vivo skin wound healing experiments also confirmed AZI@GO-PEI-CA could highly reduce the risk of S. aureus infection and accelerate wound healing. Therefore, this multicomponent antibacterial agent with synergistic antibacterial mechanism is very promising in the treatment of bacterial infection.