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The emergence of biofilm-associated resistance of microbes to traditional antibiotics has resulted in an urgent need for novel antimicrobial agents. Herein we developed a facile approach to overcome the problem through chitosan–streptomycin gold nanoparticles (CA NPs). The synthesized CA NPs were characterized by ultraviolet-visible absorption spectra (UV-vis), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS). The resulting CA NPs maintained their antibiofilm activities towards Gram-positive organisms. More importantly, CA NPs damaged established biofilms and inhibited biofilm formation of Gram-negative bacteria pathogens. Mechanistic insight demonstrated that CA NPs rendered streptomycin more accessible to biofilms, thereby it was available to interact with biofilm bacteria. Additionally, CA NPs were observed to kill more biofilm-dispersed cells than CS conjugate or streptomycin and inhibit the planktonic cell growth of Gram-positive and -negative bacteria. Thus, this work represents an innovative strategy whereby gold nanoparticles linked to carbohydrate–antibiotic conjugates can overcome antibiotic resistance of microbial biofilms, suggesting the potential of using the generated CA NPs as antimicrobial agents for bacterial infectious diseases.

Most chronic infections are difficult to eradicate because bacteria capable of surviving in host-infected cells may be protected from the killing actions of antibiotics, leading to therapy failures and disease relapses. Here we demonstrated that covalent-coupling chitosan to streptomycin significantly improved intracellular bactericidal capacity towards multiple organisms within phagocytic or nonphagocytic cells. Structure-activity relationship investigations indicated that antibiotic contents, molecular size and positive charges of the conjugate were the key to retain this intracellular bactericidal activity. Mechanistic insight demonstrated the conjugate was capable to target and eliminate endocytic or endosomal escaped bacteria through facilitating the direct contact between the antibiotic and intracellular organism. In vivo acute infection models indicated that compared to equal dose of the antibiotic, chitosan-streptomycin (C-S) conjugate and especially the human serum album binding chitosan-streptomycin conjugate (HCS) complex formed by human serum album and C-S conjugate greatly decreased the bacteria burden in the spleen and liver in both wild type and immuno-suppressive mice. Furthermore, the HCS complex remarkably reduced mortality of infected TLR2 deficient mice, mimicking immune-compromised persons who were more susceptible to bacterial infections. These findings might open up a new avenue to combat intracellular bacterial infection by aminoglycosides antibiotics at a lower effective dose.

Bacteria on living or inert surfaces usually form biofilms which make them highly resistant to antibiotics and immune clearance. Herein, we develop a simple approach to overcome the above conundrum through lysozyme-associated liposomal gentamicin (LLG). The association of lysozyme to the surface of liposomes can effectively reduce the fusion of liposomes and undesirable payload release in regular storage or physiological environments. The LLG was more effective at damaging established biofilms and inhibiting biofilm formation of pathogens including Gram-positive and Gram-negative bacteria than gentamicin alone. This strategy may provide a novel approach to treat infections due to bacterial biofilm.