Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation
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...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2019.1615848 |
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| author | Claire Siebert Helena Lindgren Sabrina Ferré Corinne Villers Sandrine Boisset Julien Perard Anders Sjöstedt Max Maurin Céline Brochier-Armanet Yohann Couté Patricia Renesto |
| author_facet | Claire Siebert Helena Lindgren Sabrina Ferré Corinne Villers Sandrine Boisset Julien Perard Anders Sjöstedt Max Maurin Céline Brochier-Armanet Yohann Couté Patricia Renesto |
| author_sort | Claire Siebert |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0428d34834be4f76b1cbc00e4e120bd3 |
| institution | OA Journals |
| issn | 2222-1751 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj-art-0428d34834be4f76b1cbc00e4e120bd32025-08-20T02:08:14ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512019-01-018180882210.1080/22221751.2019.1615848Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formationClaire Siebert0Helena Lindgren1Sabrina Ferré2Corinne Villers3Sandrine Boisset4Julien Perard5Anders Sjöstedt6Max Maurin7Céline Brochier-Armanet8Yohann Couté9Patricia Renesto10TIMC-IMAG UMR 5525 - UGA CNRS, Grenoble, FranceLaboratory for Molecular Infection Medicine Sweden and Department of Clinical Microbiology, Umeå University, Umeå, SwedenUniversité Grenoble Alpes, CEA, Inserm, IRIG-BGE, Grenoble, FranceTIMC-IMAG UMR 5525 - UGA CNRS, Grenoble, FranceTIMC-IMAG UMR 5525 - UGA CNRS, Grenoble, FranceUniversité Grenoble Alpes, CNRS, CEA, BIG-LCBM, Grenoble, FranceLaboratory for Molecular Infection Medicine Sweden and Department of Clinical Microbiology, Umeå University, Umeå, SwedenTIMC-IMAG UMR 5525 - UGA CNRS, Grenoble, FranceLaboratoire de Biométrie et Biologie Évolutive, Université Claude Bernard Lyon 1, CNRS, UMR5558, Villeurbanne, FranceUniversité Grenoble Alpes, CEA, Inserm, IRIG-BGE, Grenoble, FranceTIMC-IMAG UMR 5525 - UGA CNRS, Grenoble, FranceFrancisella 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.https://www.tandfonline.com/doi/10.1080/22221751.2019.1615848FrancisellaOMVsbiofilmsantibioticsfluoroquinolones |
| spellingShingle | Claire Siebert Helena Lindgren Sabrina Ferré Corinne Villers Sandrine Boisset Julien Perard Anders Sjöstedt Max Maurin Céline Brochier-Armanet Yohann Couté Patricia Renesto Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation Emerging Microbes and Infections Francisella OMVs biofilms antibiotics fluoroquinolones |
| title | Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation |
| title_full | Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation |
| title_fullStr | Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation |
| title_full_unstemmed | Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation |
| title_short | Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation |
| title_sort | francisella tularensis fupa mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation |
| topic | Francisella OMVs biofilms antibiotics fluoroquinolones |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2019.1615848 |
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