Deprivation of the Periplasmic Chaperone SurA Reduces Virulence and Restores Antibiotic Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa
Pseudomonas aeruginosa is one of the main causative agents of nosocomial infections and the spread of multidrug-resistant strains is rising. Therefore, novel strategies for therapy are urgently required. The outer membrane composition of Gram-negative pathogens and especially of Pa restricts the eff...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2019.00100/full |
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| author | Kristina Klein Michael S. Sonnabend Lisa Frank Karolin Leibiger Mirita Franz-Wachtel Boris Macek Thomas Trunk Jack C. Leo Ingo B. Autenrieth Monika Schütz Erwin Bohn |
| author_facet | Kristina Klein Michael S. Sonnabend Lisa Frank Karolin Leibiger Mirita Franz-Wachtel Boris Macek Thomas Trunk Jack C. Leo Ingo B. Autenrieth Monika Schütz Erwin Bohn |
| author_sort | Kristina Klein |
| collection | DOAJ |
| description | Pseudomonas aeruginosa is one of the main causative agents of nosocomial infections and the spread of multidrug-resistant strains is rising. Therefore, novel strategies for therapy are urgently required. The outer membrane composition of Gram-negative pathogens and especially of Pa restricts the efficacy of antibiotic entry into the cell and determines virulence. For efficient outer membrane protein biogenesis, the β-barrel assembly machinery (BAM) complex in the outer membrane and periplasmic chaperones like Skp and SurA are crucial. Previous studies indicated that the importance of individual proteins involved in outer membrane protein biogenesis may vary between different Gram-negative species. In addition, since multidrug-resistant Pa strains pose a serious global threat, the interference with both virulence and antibiotic resistance by disturbing outer membrane protein biogenesis might be a new strategy to cope with this challenge. Therefore, deletion mutants of the non-essential BAM complex components bamB and bamC, of the skp homolog hlpA as well as a conditional mutant of surA were investigated. The most profound effects for both traits were associated with reduced levels of SurA, characterized by increased membrane permeability, enhanced sensitivity to antibiotic treatment and attenuation of virulence in a Galleria mellonella infection model. Strikingly, the depletion of SurA in a multidrug-resistant clinical bloodstream isolate re-sensitized the strain to antibiotic treatment. From our data we conclude that SurA of Pa serves as a promising target for developing a drug that shows antiinfective activity and re-sensitizes multidrug-resistant strains to antibiotics. |
| first_indexed | 2024-12-23T11:55:52Z |
| format | Article |
| id | doaj.art-9003bc4387ba4c56929e62193d171643 |
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| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-23T11:55:52Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-9003bc4387ba4c56929e62193d1716432022-12-21T17:48:05ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2019-02-011010.3389/fmicb.2019.00100439414Deprivation of the Periplasmic Chaperone SurA Reduces Virulence and Restores Antibiotic Susceptibility of Multidrug-Resistant Pseudomonas aeruginosaKristina Klein0Michael S. Sonnabend1Lisa Frank2Karolin Leibiger3Mirita Franz-Wachtel4Boris Macek5Thomas Trunk6Jack C. Leo7Ingo B. Autenrieth8Monika Schütz9Erwin Bohn10Interfakultäres Institut für Mikrobiologie und Infektionsmedizin Tübingen (IMIT), Institut für Medizinische Mikrobiologie und Hygiene, Universität Tübingen, Tübingen, GermanyInterfakultäres Institut für Mikrobiologie und Infektionsmedizin Tübingen (IMIT), Institut für Medizinische Mikrobiologie und Hygiene, Universität Tübingen, Tübingen, GermanyInterfakultäres Institut für Mikrobiologie und Infektionsmedizin Tübingen (IMIT), Institut für Medizinische Mikrobiologie und Hygiene, Universität Tübingen, Tübingen, GermanyInterfakultäres Institut für Mikrobiologie und Infektionsmedizin Tübingen (IMIT), Institut für Medizinische Mikrobiologie und Hygiene, Universität Tübingen, Tübingen, GermanyProteome Center Tübingen, Universität Tübingen, Tübingen, GermanyProteome Center Tübingen, Universität Tübingen, Tübingen, GermanySection for Genetics and Evolutionary Biology, Department of Biosciences, University of Oslo, Oslo, NorwaySection for Genetics and Evolutionary Biology, Department of Biosciences, University of Oslo, Oslo, NorwayInterfakultäres Institut für Mikrobiologie und Infektionsmedizin Tübingen (IMIT), Institut für Medizinische Mikrobiologie und Hygiene, Universität Tübingen, Tübingen, GermanyInterfakultäres Institut für Mikrobiologie und Infektionsmedizin Tübingen (IMIT), Institut für Medizinische Mikrobiologie und Hygiene, Universität Tübingen, Tübingen, GermanyInterfakultäres Institut für Mikrobiologie und Infektionsmedizin Tübingen (IMIT), Institut für Medizinische Mikrobiologie und Hygiene, Universität Tübingen, Tübingen, GermanyPseudomonas aeruginosa is one of the main causative agents of nosocomial infections and the spread of multidrug-resistant strains is rising. Therefore, novel strategies for therapy are urgently required. The outer membrane composition of Gram-negative pathogens and especially of Pa restricts the efficacy of antibiotic entry into the cell and determines virulence. For efficient outer membrane protein biogenesis, the β-barrel assembly machinery (BAM) complex in the outer membrane and periplasmic chaperones like Skp and SurA are crucial. Previous studies indicated that the importance of individual proteins involved in outer membrane protein biogenesis may vary between different Gram-negative species. In addition, since multidrug-resistant Pa strains pose a serious global threat, the interference with both virulence and antibiotic resistance by disturbing outer membrane protein biogenesis might be a new strategy to cope with this challenge. Therefore, deletion mutants of the non-essential BAM complex components bamB and bamC, of the skp homolog hlpA as well as a conditional mutant of surA were investigated. The most profound effects for both traits were associated with reduced levels of SurA, characterized by increased membrane permeability, enhanced sensitivity to antibiotic treatment and attenuation of virulence in a Galleria mellonella infection model. Strikingly, the depletion of SurA in a multidrug-resistant clinical bloodstream isolate re-sensitized the strain to antibiotic treatment. From our data we conclude that SurA of Pa serves as a promising target for developing a drug that shows antiinfective activity and re-sensitizes multidrug-resistant strains to antibiotics.https://www.frontiersin.org/article/10.3389/fmicb.2019.00100/fullSurAPseudomonas aeruginosavirulencemultidrug resistanceantibioticsouter membrane protein biogenesis |
| spellingShingle | Kristina Klein Michael S. Sonnabend Lisa Frank Karolin Leibiger Mirita Franz-Wachtel Boris Macek Thomas Trunk Jack C. Leo Ingo B. Autenrieth Monika Schütz Erwin Bohn Deprivation of the Periplasmic Chaperone SurA Reduces Virulence and Restores Antibiotic Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa Frontiers in Microbiology SurA Pseudomonas aeruginosa virulence multidrug resistance antibiotics outer membrane protein biogenesis |
| title | Deprivation of the Periplasmic Chaperone SurA Reduces Virulence and Restores Antibiotic Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa |
| title_full | Deprivation of the Periplasmic Chaperone SurA Reduces Virulence and Restores Antibiotic Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa |
| title_fullStr | Deprivation of the Periplasmic Chaperone SurA Reduces Virulence and Restores Antibiotic Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa |
| title_full_unstemmed | Deprivation of the Periplasmic Chaperone SurA Reduces Virulence and Restores Antibiotic Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa |
| title_short | Deprivation of the Periplasmic Chaperone SurA Reduces Virulence and Restores Antibiotic Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa |
| title_sort | deprivation of the periplasmic chaperone sura reduces virulence and restores antibiotic susceptibility of multidrug resistant pseudomonas aeruginosa |
| topic | SurA Pseudomonas aeruginosa virulence multidrug resistance antibiotics outer membrane protein biogenesis |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2019.00100/full |
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