Probing transport of fosfomycin through substrate specific OprO and OprP from Pseudomonas aeruginosa

• Published in: Biochemical and biophysical research communications 2018-01, Vol.495 (1), p.1454-1460
• Main Authors: Citak, Funda, Ghai, Ishan, Rosenkötter, Frank, Benier, Lorraine, Winterhalter, Mathias, Wagner, Richard
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANTIBIOTICS; Bacterial Proteins - metabolism; Cell Membrane Permeability - physiology; CELL WALL; Fosfomycin - pharmacokinetics; Metabolic Flux Analysis - methods; Molecular Probe Techniques; PHOSPHONIC ACIDS; PORINS; Porins - metabolism; PSEUDOMONAS; Pseudomonas aeruginosa - metabolism; Substrate Specificity - physiology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.11.188

Increasing antimicrobial drug resistance is a global threat especially with respect to Gram-negative bacteria. The low permeability of the bacterial outer cell wall has been identified as an important bottleneck that prevents a sufficient antibacterial effect to be achieved at low doses of the antibiotics. In particular, the outer membrane permeability for negatively charged molecules of the clinical important ESKAPE bacterium Pseudomonas aeruginosa is determined by the low conductance porins OprO and OprP Here we show that the alternative phosphonic-acid antibiotic fosfomycin is highly permeable through the OprO and OprP channels. For this, we applied an electrophysiological zero-current assay using concentration gradients of fosfomycin under tri-ionic conditions to quantify flux of fosfomycin through OprO and OprP. Our analyzes show that OprO, and to a lesser degree OprP, have unexpected very high permeability to fosfomycin, so the antibiotic should be a potentially excellent alternative choice for the control of Pseudomonas aeruginosa infections.