Enhanced Synergistic Antibacterial and Antibiofilm Efficacy of Main-Chain Polysulfoniums with Antibiotics by Balancing Charge Density and Amphiphilicity

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.