Biology subjects

Luscher, A.

Publications and source records attributed to Luscher, A..

3 recordsLinked to original sources

bioRxiv2026

Auranofin shows bactericidal activity in Pseudomonas aeruginosa by targeting thiol homeostasis

The intrinsic resistance of Pseudomonas aeruginosa to many antibiotics is driven by the combined action of the outer membrane permeability barrier and multidrug efflux pumps, limiting the discovery of compounds active against this pathogen. To facilitate identification of antibacterial molecules with intracellular targets, we constructed a hyper-permeable P. aeruginosa PA14 strain lacking the four major Mex efflux systems and expressing the FhuA-derived hyperpore. This strain exhibited markedly increased susceptibility to diverse antimicrobials. Screening of 2,400 predominantly FDA-approved compounds identified the antirheumatic drug auranofin as a potent inhibitor which displayed bactericidal activity against the hyperpermeable strain. Selection of resistant mutants identified gain-of-function mutations in the MexQ efflux pump, indicating that altered substrate specificity of the MexP-MexQ-OpmE efflux system can reduce auranofin susceptibility. To investigate its mode of action, we analyzed mutants defective in the thioredoxin and glutathione redox systems. Whereas disruption of the thioredoxin pathway had no effect on susceptibility, glutathione-deficient mutants were hypersusceptible to auranofin. Exogenous glutathione restored resistance, and intracellular thiol measurements demonstrated that auranofin depletes the cellular thiol pool, consistent with direct neutralization by glutathione. These findings support a model in which auranofin disrupts glutathione-dependent thiol homeostasis in P. aeruginosa. More broadly, our study demonstrates that overcoming permeability and efflux barriers is an effective strategy to reveal antibacterial activities of approved drugs against Gram-negative pathogens.

microbiology↗

bioRxiv2026

Adaptation of Pseudomonas aeruginosa to the lung allograft environment in cystic fibrosis lung transplant recipients

Lung transplantation (LT) is the ultimate treatment option for patients suffering from end stage cystic fibrosis (CF). Most LT-patients, colonized pre-LT by Pseudomonas aeruginosa witness colonization of their non-CF allograft within a few days or weeks post-LT, thereby compromising graft and life expectancy. How P. aeruginosa isolates adapted for years to the specific CF lung environment efficiently colonize and survive in the non-CF allograft environment remains unclear. To address this question, we collected sequential isolates from CF LT-recipients and non-CF LT-recipients and performed phenotypic and genetic analyses of pairs of early and late isolates from LT-patients. We found evidence for mutations compatible with a switch from biofilm to planktonic lifestyle as well as loss of mucoid phenotypes. Hypermutators, characteristic of chronic CF-adapted isolates, were also found in four LT-patients. Their persistence in the non-CF allograft environment suggests a continuous seeding from the sinuses. Our results suggest that in CF LT-recipients efficient colonisation by P. aeruginosa of the allograft implies both adaptation and continuous seeding from the sinuses to the lower respiratory tract.

microbiology↗

bioRxiv2019

Lowe Syndrome-linked endocytic adaptors direct membrane cycling kinetics with OCRL in Dictyostelium discoideum.

Mutations of the inositol 5-phosphatase OCRL cause Lowe Syndrome (LS), characterized by congenital cataract, low IQ and defective kidney proximal tubule resorption. A key subset of LS mutants abolishes OCRLs interactions with endocytic adaptors containing F&H peptide motifs. Converging unbiased methods examining human peptides and the unicellular phagocytic organism Dictyostelium discoideum, reveal that, like OCRL, the Dictyostelium OCRL orthologue Dd5P4 binds two proteins closely related to the F&H proteins APPL1 and Ses1/2 (also referred to as IPIP27A/B). In addition, a novel conserved F&H interactor was identified, GxcU (in Dictyostelium) and the Cdc42-GEF Frabin (in human cells). Examining these proteins in Dictyostelium discoideum, we find that, like OCRL, Dd5P4 acts at well-conserved and physically distinct endocytic stations. Dd5P4 functions in coordination with F&H proteins to control membrane deformation at multiple stages of endocytosis, and suppresses GxcU-mediated activity during fluid-phase micropinocytosis. We also reveal that OCRL/Dd5P4 acts at the contractile vacuole, an exocytic osmoregulatory organelle. We propose F&H peptide-containing proteins may be key modifiers of LS phenotypes.

cell biology↗