Roles of Salmonella multidrug efflux pumps in tigecycline resistance

Salmonella enterica strains exhibiting decreased susceptibility to tigecycline have been reported. In this study, we sought to elucidate the roles of Salmonella multidrug efflux pumps and AcrAB regulators in tigecycline resistance. We examined the involvement of multidrug efflux pumps and AcrAB regulators in resistance to tigecycline and other glycylcyclines by determining the MICs of the drugs for Salmonella multidrug efflux pump and AcrAB regulator-overproducing or -deleted strains. Strains of S. enterica serovar Typhimurium derived from the wild-type strain ATCC 14028s were used in this study. A plasmid carrying the tet gene conferred resistance to 9-(N,N-dimethylglycylamido)-6-demethyl-6-deoxytetracycline ('DMG-DMDOT') minocycline, doxycycline and tetracycline, but does not affect tigecycline resistance. Deletion of acrAB resulted in strains with significantly increased susceptibility to tigecycline and other glycylcyclines. Plasmids carrying the acrAB or acrEF gene restored increased susceptibility of the acrAB-deleted mutant to all tested compounds. Deletion of ramA, a positive regulator of acrAB, slightly increased susceptibility to tigecycline. Overexpression of ramA and deletion of ramR, a repressor of ramA, resulted in decreased susceptibility to all tested compounds. This phenotype, modulated by ramA or ramR, was not observed in the acrB-deleted background. AcrAB and AcrEF confer resistance to tigecycline and tetracycline derivatives in Salmonella. RamA and RamR are also involved in resistance to tigecycline in an AcrAB-dependent manner.