title: Recognition of mechanisms involved in bile resistance important to halting antimicrobial resistance in nontyphoidal Salmonella.
abstract: Increasing antimicrobial resistance in nontyphoidal Salmonella (NTS) is a global public health problem that complicates antimicrobial therapy. As an enteric pathogen, Salmonella must endure the presence of bile in the intestinal tract during the course of infection. In this study, we sought to identify Salmonella genes necessary for bile resistance and to investigate their association with antimicrobial resistance. Four genes related to bile resistance were identified, namely rfaP, rfbK, dam and tolC. The first three genes are involved in lipopolysaccharide synthesis, and tolC is associated with an efflux pump. Antimicrobial susceptibility testing showed increased susceptibility to polymyxin B and ciprofloxacin in rfaP and tolC mutants of Salmonella, respectively. Genetic analysis of 45 clinical isolates of NTS revealed that all isolates with reduced susceptibility to fluoroquinolones (minimum inhibitory concentration ≥0.125 mg/L) were associated with point mutations in the quinolone resistance-determining regions of the gyrA and parC genes. The efflux pump also played a role, as evidenced by the reduction in fluoroquinolone resistance when the TolC efflux pump was inhibited by Phe-Arg-β-naphthylamide, a competitive efflux pump inhibitor. Based on these results, we conclude that an intact membrane structure and the efflux pump system provide mechanisms enabling NTS to resist bile. Caution should be taken when using ciprofloxacin and polymyxin B to treat Salmonella enteric infection, as resistance to these agents involves the same mechanisms. Addition of an efflux pump inhibitor to fluoroquinolones may be an effective strategy to deal with the increasing resistance in NTS.
authors: Department of Pediatrics, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors: Ming-Han
authors: MH
authors: Tsai
authors: Sih-Ru
authors: SR
authors: Wu
authors: Hao-Yuan
authors: HY
authors: Lee
authors: Chyi-Liang
authors: CL
authors: Chen
authors: Tzou-Yien
authors: TY
authors: Lin
authors: Yhu-Chering
authors: YC
authors: Huang
authors: Cheng-Hsun
authors: CH
authors: Chiu
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D058491:Bacterial Load; D001646:Bile / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002939:Ciprofloxacin / Q000494:pharmacology; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D005243:Feces / Q000382:microbiology; D005798:Genes, Bacterial; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D017354:Point Mutation; D011112:Polymyxin B / Q000494:pharmacology; D015203:Reproducibility of Results; D012475:Salmonella / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D026901:Membrane Transport Proteins; D002939:Ciprofloxacin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D011112:Polymyxin B