title: Resistance of the Burkholderia cepacia complex to fosmidomycin and fosmidomycin derivatives.
abstract: The Burkholderia cepacia complex (BCC) is a group of 17 closely related opportunistic pathogens that are able to infect the respiratory tract of cystic fibrosis patients. BCC bacteria are intrinsically resistant to many antibiotics and are therefore difficult to eradicate. Fosmidomycin could be a new therapeutic agent to treat BCC infections as it inhibits 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in the non-mevalonate pathway essential in BCC bacteria for isoprenoid synthesis. In this study, the antimicrobial activity of fosmidomycin and eight fosmidomycin derivatives towards 40 BCC strains was investigated. All BCC strains were resistant to fosmidomycin, although addition of glucose-6-phosphate reduced the minimum inhibitory concentration values of FR900098, the fosmidomycin acetyl derivative, from 512 mg/L to 64 mg/L for Burkholderia multivorans and B. cepacia. This enhanced activity was linked to increased expression of the genes involved in glycerol-3-phosphate transport, which appears to be the only route for fosmidomycin import in BCC bacteria. Furthermore, upregulation of a fosmidomycin resistance gene (fsr) encoding an efflux pump was observed during fosmidomycin and FR900098 treatment. These results strongly suggest that the observed resistance in BCC bacteria is due to insufficient uptake accompanied by fosmidomycin and FR900098 efflux.
authors: Laboratory of Pharmaceutical Microbiology, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
authors: Anne-Sophie
authors: AS
authors: Messiaen
authors: Thomas
authors: T
authors: Verbrugghen
authors: Charlotte
authors: C
authors: Declerck
authors: Regina
authors: R
authors: Ortmann
authors: Martin
authors: M
authors: Schlitzer
authors: Hans
authors: H
authors: Nelis
authors: Serge
authors: S
authors: Van Calenbergh
authors: Tom
authors: T
authors: Coenye
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D042602:Burkholderia cepacia complex / Q000187:drug effects*; D024881:Drug Resistance, Bacterial; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D015854:Up-Regulation
chemical_list: D000900:Anti-Bacterial Agents; D026901:Membrane Transport Proteins; D005578:Fosfomycin; C024640:fosmidomycin