title: Pseudomonas aeruginosa fosfomycin resistance mechanisms affect non-inherited fluoroquinolone tolerance.
abstract: Pseudomonas aeruginosa is an opportunistic pathogen that poses a threat in clinical settings due to its intrinsic and acquired resistance to a wide spectrum of antibiotics. Additionally, the presence of a subpopulation of cells surviving high concentrations of antibiotics, called persisters, makes it virtually impossible to eradicate a chronic infection. The mechanism underlying persistence is still unclear, partly due to the fact that it is a non-inherited phenotype. Based on our findings from a previously performed screening effort for P. aeruginosa persistence genes, we hypothesize that crosstalk can occur between two clinically relevant mechanisms: the persistence phenomenon and antibiotic resistance. This was tested by determining the persistence phenotype of P. aeruginosa strains that are resistant to the antibiotic fosfomycin due to either of two unrelated fosfomycin resistance mechanisms. Overexpression of fosA (PA1129) confers fosfomycin resistance by enzymic modification of the antibiotic, and in addition causes a decrease in the number of persister cells surviving ofloxacin treatment. Both phenotypes require the enzymic function of FosA, as mutation of the Arg119 residue abolishes fosfomycin resistance as well as low persistence. The role for fosfomycin resistance mechanisms in persistence is corroborated by demonstrating a similar phenotype in a strain with a mutation in glpT (PA5235), which encodes a glycerol-3-phosphate transporter essential for fosfomycin uptake. These results indicate that fosfomycin resistance, conferred by glpT mutation or by overexpression of fosA, results in a decrease in the number of persister cells after treatment with ofloxacin and additionally stress that further research into the interplay between fosfomycin resistance and persistence is warranted.
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Valerie N
authors.initials: VN
authors.lastname: De Groote
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Fauvart
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Cyrielle I
authors.initials: CI
authors.lastname: Kint
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: Verstraeten
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Jans
authors.affiliation: Department of Molecular and Cellular Interactions, Laboratory of Microbial Interactions, Flanders Interuniversity Institute for Biotechnology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cornelis
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Michiels
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004361:Drug Tolerance; D024841:Fluoroquinolones / Q000494:pharmacology*; D005578:Fosfomycin / Q000494:pharmacology*; D015870:Gene Expression; D005798:Genes, Bacterial; D005994:Glycerophosphates / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D050296:Microbial Viability / Q000187:drug effects; D015242:Ofloxacin / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D005994:Glycerophosphates; D026901:Membrane Transport Proteins; D005578:Fosfomycin; D015242:Ofloxacin