Incorporation of cationic groups into polymers represents one of the most widely used strategies to prepare antibacterial materials. Sulfonium, as a typical cationic moiety, displays potent antibacterial efficacy in the form of small molecules, however, has long underperformed in polymeric systems. Herein, we developed a series of alternating polysulfoniums, where the hydrophobicity of each alternating unit can be accurately tuned by altering the monomer precursors. Excellent antibacterial activity against a broad spectrum of clinically relevant bacteria, including Methicillin-resistant Staphylococcus aureus, can be obtained in the optimal compositions with minimum bactericidal concentrations in the range of 1.25−10 μg/mL, as well as negligible hemolytic effect at polymer concentrations even up to 10000 μg/mL. Bacteria do not readily develop resistance to polysulfoniums due to the antibacterial action is possibly the membrane disrupting mechanism. This work demonstrates sulfoniumbased polymers with well-defined sequences can function as a promising candidate to combat drug-resistant bacterial infection.

Unlike antibiotics with accurate chemical structures, polydisperse chain lengths of synthetic polycations usually result in undesirable variations of antibacterial performance, which obstructs their wide applications in many areas. Herein, we propose that main-chain sulfonium-based polymers with alternating sequences may be used as a potential solution to tackle this issue. Through the thiol–epoxy “click” step-growth polymerization and methylation, alternating polysulfoniums can be facilely prepared with polydispersity around 1.5 and a molecular weight ranging from 6000 to 50 000 g/mol. Within this tested range, constant minimum bactericidal concentration (MBC) values against a broad spectrum of clinically relevant bacteria and stable hemocompatibility are observed for polysulfoniums with different chemical compositions. Moreover, the representative polysulfonium can steadily inhibit the biofilm formation (∼75–90%) at 1.25–5 μg/mL and achieve 97–99.9% reduction of bacteria at 10–40 μg/mL in the 3 day mature biofilms. We hypothesize that the amphiphilicity of main-chain polysulfoniums displays less susceptibility to the dispersed polymer chains, probably because of their accurate alternating sequence and the location of all functional groups in the polymer main chain. The unique structural nature of the main-chain sulfonium-based alternating polymers can make them serve as a reliable platform for antibacterial applications in the field of synthetic polycations.

Infection diseases caused by Gram-negative pathogens are exceedingly difficult to treat because their characteristic outer membrane limits antibiotic entry. Herein, we report the development of main-chain polysulfoniums with different charge densities and amphiphilicities based on the quantitative methylation reaction. By regulating the membrane-disruption capability, the combined efficacy of polysulfoniums and antibiotic rifampicin can be manipulated from no interaction to synergy against Gram-negative bacteria Escherichia coli. After incubating with synergistic polysulfoniums/rifampicin combinations at a minimum inhibitory concentration (MIC), the time needed to achieve a 6-log reduction of E. coli can be accelerated 8 times compared to the antibiotic treatment. At 1/2 MIC, polysulfoniums/rifampicin combinations can provide a 90% reduction in biofilm mass and 8-log orders of embedded bacteria killing in 3-day-mature E. coli biofilms. This work demonstrates that alkylation chemistry can serve as a reliable means to create antibiotic adjuvants in combating infections caused by Gram-negative pathogens and biofilms.

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