Restoration of antibiotic susceptibility in fluoroquinolone-resistant Escherichia coli by targeting acrB with antisense phosphorothioate oligonucleotide encapsulated in novel anion liposome

Abstract

Fluoroquinolone-resistant Escherichia coli (FREC) is one of the leading causes of Gram-negative bacterial infections short of effective antibiotics, thus necessitating development of novel antibacterial agents such as antisense resistance inhibitors. Aiming to restore susceptibility of FREC to fluoroquinolones by antisense inhibition of essential resistance mechanism, we designed and synthesized anion liposome encapsulated phosphorothioate oligodeoxynucleotide 831 (PS-ODN831) targeting gene acrB, which encodes the AcrAB-TolC efflux pump responsible for decreasing intercellular antibiotic concentrations. In all encapsulated PS-ODN831-treated groups, the MICs of ciprofloxacin and levofloxacin to FREC were reduced at different degrees, therefore inhibiting growth of FREC in a concentration-dependent manner. Reversion of their bactericidal effects was the result of specific and potent inhibition of acrB mRNA and the activity of efflux pump of AcrAB-TolC in FREC strains by liposome-encapsulated PS-ODN831. The study indicated that antisense targeting of AcrAB-TolC efflux pump system may be a feasible and potential strategy to treat FREC infections.