title: Efflux pumps may play a role in tigecycline resistance in Burkholderia species.
abstract: The purpose of this study was to investigate the role of multidrug resistance efflux pumps in relation to decreased susceptibility to tigecycline in clinical isolates of Burkholderia cepacia complex (BCC). The role of efflux pumps was analysed using the efflux pump inhibitor (EPI) MC-207,110. Minimum inhibitory concentrations (MICs) were determined for each strain against tigecycline alone and in the presence of 64 mg/L MC-207,110. The effect of efflux pump inhibition on the susceptibility of BCC isolates to tigecycline was assessed by a checkerboard titration assay. Ala-Nap uptake assay was performed to determine efflux pump activity in different strains. The checkerboard titration assay showed that the MIC decreased with increasing concentrations of EPI. MICs for tigecycline in the clinical isolates ranged between 8 mg/L and 32 mg/L, whereas in the presence of MC-207,110, MICs decreased significantly (range <0.125-1.0mg/L; 16 to >256 times reduction). Efflux pump activity was shown to be greatest in strains with the highest MIC and vice versa. In conclusion, BCC possess efflux pumps that influence their resistance to tigecycline. Use of an inhibitor of these pumps restored sensitivity to the antibiotic. Therefore, a combination of tigecycline and EPI to augment its efficacy may present an attractive therapeutic option.
authors.affiliation: Section of Infection and Immunity, Glasgow Dental School, Faculty of Medicine, University of Glasgow, 378 Sauchiehall Street, Glasgow G2 3JZ, UK.
authors.forename: Ranjith
authors.initials: R
authors.lastname: Rajendran
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Quinn
authors.forename: Colin
authors.initials: C
authors.lastname: Murray
authors.forename: Elaine
authors.initials: E
authors.lastname: McCulloch
authors.forename: Craig
authors.initials: C
authors.lastname: Williams
authors.forename: Gordon
authors.initials: G
authors.lastname: Ramage
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D019121:Burkholderia Infections / Q000382:microbiology; D042602:Burkholderia cepacia complex / Q000187:drug effects* / Q000502:physiology; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008911:Minocycline; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000078304:Tigecycline