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 Arg 119 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.

Pseudomonas aeruginosa Biofilms in Disease

“…Moker and colleagues found that pyocanin, paraquot and the acyl-homoserine lactone 3-OC12-HSL slightly increased persister formation in exponentially growing cutlures of P. aeruginosa, but not in E. coli or S. aureus cultures [100]. De Groote et al discovered that strains with fosfomycin resistance correlated with decreased tolerance to fluoroquinolones [101]. The reasons for this correlation are still unclear, but a simple assumption is that fosfomycin resistance has a fitness cost on cells that affects susceptibility or tolerance to other antibiotics.…”

Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies

“…Surprisingly then, a recent study revealed the involvement of antibiotic resistance mechanisms in persistence. Knockout mutations of fosA and glpT, both resulting in increased resistance against fosfomycin, gave rise to decreased persistence (De Groote et al, 2011). GlpT was originally identified as a glycerol-3-phosphate (G3P) transporter in E. coli, but is also able to transport glycerol 2-phosphate (G2P) and fosfomycin into the bacterial cell, illustrating its relatively low substrate specificity (Law et al, 2009).…”

Fosfomycin: Mechanism and Resistance

“…It would seem critically important to study the conditions under which fosA is expressed in P. aeruginosa, to ascertain what its effect is on basal MICs and whether sufficient expression to yield a resistant phenotype can be achieved by mutation or induction. One reference (De Groote et al 2011) notes that fosfomycin resistance in P. aeruginosa can be caused by (engineered) overexpression of the resident FosA because of an inserted promoter. Whether turn-on of FosA in P. aeruginosa is a possible source of mutational resistance is not known.…”