Glutathione-Responsive Sulfur Dioxide-Releasing Dendronized Chitooligosaccharide Polymer for Effective Treatment of Multidrug-Resistant Bacterial Infection

Treating bacterial infection is emerging as a major obstacle to human public health today. As a kind of long-established and widely used food preservative, the lipophilic gas sulfur dioxide (SO2) has been shown a broad-spectrum antimicrobial property, moreover, the endogenous physiological effects of SO2 found in mammals in recent years further suggest its biological tolerance. However, the uncontrolled release and inconvenienced storage of free SO2 gas limit its biological antibacterial applications. Herein, we constructed a water-soluble dendronized chitooligosaccharide polymer Cos-G3-Dns with glutathione-responsive SO2-releasing property via a one-step copper-catalyzed azide-alkyne click reaction for antibacterial application. The polymer Cos-G3-Dns exhibited remarkable antibacterial activity in vitro against Gram-positive bacteria Staphylococcus aureus (S. aureus), methicillin-resistant S. aureus (MRSA) and Gram-negative bacteria Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa). The effective antibacterial effect of Cos-G3-Dns was also demonstrated in vivo by the Caenorhabditis elegans (C. elegans) MRSA-infection model assay. Moreover, Cos-G3-Dns displayed high biocompatibility, as no significant cytotoxicity and hemolysis of Cos-G3-Dns were observed at the effective antimicrobial concentration. Preliminary antibacterial mechanism studies revealed that Cos-G3-Dns did not affect bacterial membrane permeability, but induced elevated reactive oxygen species levels and the depletion of antioxidant thiols might play a key role.