title: Fosmidomycin decreases membrane hopanoids and potentiates the effects of colistin on Burkholderia multivorans clinical isolates.
abstract: Burkholderia cepacia complex (Bcc) pulmonary infections in people living with cystic fibrosis (CF) are difficult to treat because of the extreme intrinsic resistance of most isolates to a broad range of antimicrobials. Fosmidomycin is an antibacterial and antiparasitic agent that disrupts the isoprenoid biosynthesis pathway, a precursor to hopanoid biosynthesis. Hopanoids are involved in membrane stability and contribute to polymyxin resistance in Bcc bacteria. Checkerboard MIC assays determined that although isolates of the Bcc species B. multivorans were highly resistant to treatment with fosmidomycin or colistin (polymyxin E), antimicrobial synergy was observed in certain isolates when the antimicrobials were used in combination. Treatment with fosmidomycin decreased the MIC of colistin for isolates as much as 64-fold to as low as 8 μg/ml, a concentration achievable with colistin inhalation therapy. A liquid chromatography-tandem mass spectrometry technique was developed for the accurate quantitative determination of underivatized hopanoids in total lipid extracts, and bacteriohopanetetrol cyclitol ether (BHT-CE) was found to be the dominant hopanoid made by B. multivorans. The amount of BHT-CE made was significantly reduced upon fosmidomycin treatment of the bacteria. Uptake assays with 1-N-phenylnaphthylamine were used to determine that dual treatment with fosmidomycin and colistin increases membrane permeability, while binding assays with boron-dipyrromethene-conjugated polymyxin B illustrated that the addition of fosmidomycin had no impact on polymyxin binding. This work indicates that pharmacological suppression of membrane hopanoids with fosmidomycin treatment can increase the susceptibility of certain clinical B. multivorans isolates to colistin, an agent currently in use to treat pulmonary infections in CF patients.
authors: Centre for Understanding and Preventing Infection in Children, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Rebecca J
authors: RJ
authors: Malott
authors: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors: Chia-Hung
authors: CH
authors: Wu
authors: Centre for Understanding and Preventing Infection in Children, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Tracy D
authors: TD
authors: Lee
authors: Centre for Understanding and Preventing Infection in Children, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Trevor J
authors: TJ
authors: Hird
authors: Environmental Analysis Center, California Institute of Technology, Pasadena, California, USA.
authors: Nathan F
authors: NF
authors: Dalleska
authors: Centre for Understanding and Preventing Infection in Children, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: James E A
authors: JE
authors: Zlosnik
authors: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA Howard Hughes Medical Institute, Pasadena, California, USA Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, California, USA.
authors: Dianne K
authors: DK
authors: Newman
authors: Centre for Understanding and Preventing Infection in Children, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada dspeert@cfri.ubc.ca.
authors: David P
authors: DP
authors: Speert
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019117:Burkholderia / Q000187:drug effects*; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects*; D003091:Colistin / Q000494:pharmacology*; D004357:Drug Synergism; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D053978:Pentacyclic Triterpenes / Q000032:analysis* / Q000037:antagonists & inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D053978:Pentacyclic Triterpenes; D005578:Fosfomycin; C024640:fosmidomycin; D003091:Colistin