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

Infectiondiseases caused by Gram-negative pathogensare exceedinglydifficult to treat because their characteristic outer membrane limitsantibiotic entry. Herein, we report the development of main-chainpolysulfoniums with different charge densities and amphiphilicitiesbased on the quantitative methylation reaction. By regulating themembrane-disruption capability, the combined efficacy of polysulfoniumsand antibiotic rifampicin can be manipulated from no interaction tosynergy against Gram-negative bacteria Escherichiacoli. After incubating with synergistic polysulfoniums/rifampicincombinations at a minimum inhibitory concentration (MIC), the timeneeded 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 killingin 3-day-mature E. coli biofilms. Thiswork demonstrates that alkylation chemistry can serve as a reliablemeans to create antibiotic adjuvants in combating infections causedby Gram-negative pathogens and biofilms.