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.