Archive ouverte HAL - Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation

Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation

Claire Siebert 1, 2 Héléna Lindgren 3 Sabrina Ferré 4 Corinne Villers 5, 2 Sandrine Boisset 1, 2 Julien Pérard 6, 7 Anders Sjöstedt 3 Max Maurin 1, 2 Celine Brochier-Armanet 8 Yohann Couté 4 Patricia Renesto 2, *
* Auteur correspondant
1 Centre National de Référence des Francisella [CHU Grenoble]
CHU - Centre Hospitalier Universitaire [Grenoble]
2 TIMC-IMAG-TheREx - Thérapeutique Recombinante Expérimentale
TIMC-IMAG - Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525
4 EDyP - Etude de la dynamique des protéomes
BGE - UMR S1038 - Laboratoire de Biologie à Grande Échelle
6 BIOCAT - Biocatalyse
LCBM - UMR 5249 - Laboratoire de Chimie et Biologie des Métaux
7 BioMet - Biologie des Métaux
LCBM - UMR 5249 - Laboratoire de Chimie et Biologie des Métaux
Abstract : Francisella tularensis is the causative agent in tularemia for which the high prevalence of treatment failure and relapse is a major concern. Directed-evolution experiments revealed that acquisition of fluoroquinolone (FQ) resistance was linked to factors in addition to mutations in DNA gyrase. Here, using F. tularensis live vaccine strain (LVS) as a model, we demonstrated that FupA/B (Fer-Utilization Protein) expression is linked to FQ susceptibility, and that the virulent strain F. tularensis subsp. tularensis SCHU S4 deleted for the homologous FupA protein exhibited even higher FQ resistance. In addition to an increased FQ minimal inhibitory concentration, LVSΔfupA/B displayed tolerance toward bactericidal compounds including ciprofloxacin and gentamicin. Interestingly, the FupA/B deletion was found to promote increased secretion of outer membrane vesicles (OMVs). Mass spectrometry-based quantitative proteomic characterization of vesicles from LVS and LVS∆fupA/B identified 801 proteins, including a subset of 23 proteins exhibiting differential abundance between both strains which may therefore contribute to the reduced antibiotic susceptibility of the FupA/B-deleted strain. We also demonstrated that OMVs are key structural elements of LVSΔfupA/B biofilms providing protection against FQ. These results provide a new basis for understanding and tackling antibiotic resistance and/or persistence of Francisella and other pathogenic members of the Thiotrichales class.
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https://hal.archives-ouvertes.fr/hal-02162305
Contributeur : Nathalie Gon <>
Soumis le : vendredi 21 juin 2019 - 16:10:19
Dernière modification le : lundi 14 octobre 2019 - 16:10:04

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Claire Siebert, Héléna Lindgren, Sabrina Ferré, Corinne Villers, Sandrine Boisset, et al.. Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation. Emerging microbes & infections, Earliest : Springer-Nature ; Latest : Taylor & Francis, 2019, 8 (1), pp.808-822. ⟨10.1080/22221751.2019.1615848⟩. ⟨hal-02162305⟩

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