Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus
- Autores
- Nguyen, Minh-Thu; Saising, Jongkon; Tribelli, Paula Maria; Nega, Mulugeta; Diene, Seydina M.; François, Patrice; Schrenzel, Jacques; Spröer, Cathrin; Bunk, Boyke; Ebner, Patrick; Hertlein, Tobias; Kumari, Nimerta; Härtner, Thomas; Wistuba, Dorothee; Voravuthikunchai, Supayang P.; Mäder, Ulrike; Ohlsen, Knut; Götz, Friedrich
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Rhodomyrtone (Rom) is an acylphloroglucinol antibiotic originally isolated from leaves of Rhodomyrtus tomentosa. Rom targets the bacterial membrane and is active against a wide range of Gram-positive bacteria but the exact mode of action remains obscure. Here we isolated and characterized a spontaneous Rom-resistant mutant from the model strain Staphylococcus aureus HG001 (RomR) to learn more about the resistance mechanism. We showed that Rom-resistance is based on a single point mutation in the coding region of farR [regulator of fatty acid (FA) resistance] that causes an amino acid change from Cys to Arg at position 116 in FarR, that affects FarR activity. Comparative transcriptome analysis revealed that mutated farR affects transcription of many genes in distinct pathways. FarR represses for example the expression of its own gene (farR), its flanking gene farE (effector of FA resistance), and other global regulators such as agr and sarA. All these genes were consequently upregulated in the RomR clone. Particularly the upregulation of agr and sarA leads to increased expression of virulence genes rendering the RomR clone more cytotoxic and more pathogenic in a mouse infection model. The Rom-resistance is largely due to the de-repression of farE. FarE is described as an efflux pump for linoleic and arachidonic acids. We observed an increased release of lipids in the RomR clone compared to its parental strain HG001. If farE is deleted in the RomR clone, or, if native farR is expressed in the RomR strain, the corresponding strains become hypersensitive to Rom. Overall, we show here that the high Rom-resistance is mediated by overexpression of farE in the RomR clone, that FarR is an important regulator, and that the point mutation in farR (RomR clone) makes the clone hyper-virulent.
Fil: Nguyen, Minh-Thu. Eberhard Karls Universität Tübingen.; Alemania
Fil: Saising, Jongkon. Eberhard Karls Universität Tübingen.; Alemania
Fil: Tribelli, Paula Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Eberhard Karls Universität Tübingen.; Alemania
Fil: Nega, Mulugeta. Eberhard Karls Universität Tübingen.; Alemania
Fil: Diene, Seydina M.. Geneva University Hospitals; Suiza
Fil: François, Patrice. Geneva University Hospitals; Suiza
Fil: Schrenzel, Jacques. Geneva University Hospitals; Suiza
Fil: Spröer, Cathrin. Leibniz Institute Dsmz-german Collection Of Microorgani; Alemania
Fil: Bunk, Boyke. Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH; Alemania
Fil: Ebner, Patrick. Eberhard Karls Universität Tübingen.; Alemania
Fil: Hertlein, Tobias. University Of Würzburg; Alemania
Fil: Kumari, Nimerta. Eberhard Karls Universität Tübingen.; Alemania
Fil: Härtner, Thomas. Eberhard Karls Universität Tübingen.; Alemania
Fil: Wistuba, Dorothee. Eberhard Karls Universität Tübingen.; Alemania
Fil: Voravuthikunchai, Supayang P.. Prince Of Songkla University; Tailandia
Fil: Mäder, Ulrike. University Medicine Greifswald; Alemania
Fil: Ohlsen, Knut. University Of Würzburg; Alemania
Fil: Götz, Friedrich. Eberhard Karls Universität Tübingen.; Alemania - Materia
-
ANTIBIOTIC
GRAM-POSITIVE BACTERIA
MEMBRANE ACTIVE
RHODOMYRTONE
STAPHYLOCOCCUS - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/123548
Ver los metadatos del registro completo
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Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureusNguyen, Minh-ThuSaising, JongkonTribelli, Paula MariaNega, MulugetaDiene, Seydina M.François, PatriceSchrenzel, JacquesSpröer, CathrinBunk, BoykeEbner, PatrickHertlein, TobiasKumari, NimertaHärtner, ThomasWistuba, DorotheeVoravuthikunchai, Supayang P.Mäder, UlrikeOhlsen, KnutGötz, FriedrichANTIBIOTICGRAM-POSITIVE BACTERIAMEMBRANE ACTIVERHODOMYRTONESTAPHYLOCOCCUShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Rhodomyrtone (Rom) is an acylphloroglucinol antibiotic originally isolated from leaves of Rhodomyrtus tomentosa. Rom targets the bacterial membrane and is active against a wide range of Gram-positive bacteria but the exact mode of action remains obscure. Here we isolated and characterized a spontaneous Rom-resistant mutant from the model strain Staphylococcus aureus HG001 (RomR) to learn more about the resistance mechanism. We showed that Rom-resistance is based on a single point mutation in the coding region of farR [regulator of fatty acid (FA) resistance] that causes an amino acid change from Cys to Arg at position 116 in FarR, that affects FarR activity. Comparative transcriptome analysis revealed that mutated farR affects transcription of many genes in distinct pathways. FarR represses for example the expression of its own gene (farR), its flanking gene farE (effector of FA resistance), and other global regulators such as agr and sarA. All these genes were consequently upregulated in the RomR clone. Particularly the upregulation of agr and sarA leads to increased expression of virulence genes rendering the RomR clone more cytotoxic and more pathogenic in a mouse infection model. The Rom-resistance is largely due to the de-repression of farE. FarE is described as an efflux pump for linoleic and arachidonic acids. We observed an increased release of lipids in the RomR clone compared to its parental strain HG001. If farE is deleted in the RomR clone, or, if native farR is expressed in the RomR strain, the corresponding strains become hypersensitive to Rom. Overall, we show here that the high Rom-resistance is mediated by overexpression of farE in the RomR clone, that FarR is an important regulator, and that the point mutation in farR (RomR clone) makes the clone hyper-virulent.Fil: Nguyen, Minh-Thu. Eberhard Karls Universität Tübingen.; AlemaniaFil: Saising, Jongkon. Eberhard Karls Universität Tübingen.; AlemaniaFil: Tribelli, Paula Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Eberhard Karls Universität Tübingen.; AlemaniaFil: Nega, Mulugeta. Eberhard Karls Universität Tübingen.; AlemaniaFil: Diene, Seydina M.. Geneva University Hospitals; SuizaFil: François, Patrice. Geneva University Hospitals; SuizaFil: Schrenzel, Jacques. Geneva University Hospitals; SuizaFil: Spröer, Cathrin. Leibniz Institute Dsmz-german Collection Of Microorgani; AlemaniaFil: Bunk, Boyke. Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH; AlemaniaFil: Ebner, Patrick. Eberhard Karls Universität Tübingen.; AlemaniaFil: Hertlein, Tobias. University Of Würzburg; AlemaniaFil: Kumari, Nimerta. Eberhard Karls Universität Tübingen.; AlemaniaFil: Härtner, Thomas. Eberhard Karls Universität Tübingen.; AlemaniaFil: Wistuba, Dorothee. Eberhard Karls Universität Tübingen.; AlemaniaFil: Voravuthikunchai, Supayang P.. Prince Of Songkla University; TailandiaFil: Mäder, Ulrike. University Medicine Greifswald; AlemaniaFil: Ohlsen, Knut. University Of Würzburg; AlemaniaFil: Götz, Friedrich. Eberhard Karls Universität Tübingen.; AlemaniaFrontiers Media S.A.2019-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/123548Nguyen, Minh-Thu; Saising, Jongkon; Tribelli, Paula Maria; Nega, Mulugeta; Diene, Seydina M.; et al.; Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus; Frontiers Media S.A.; Frontiers in Microbiology; 10; MAY; 5-2019; 1-141664-302XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/article/10.3389/fmicb.2019.01157/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fmicb.2019.01157info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:43:18Zoai:ri.conicet.gov.ar:11336/123548instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:43:18.589CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus |
| title |
Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus |
| spellingShingle |
Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus Nguyen, Minh-Thu ANTIBIOTIC GRAM-POSITIVE BACTERIA MEMBRANE ACTIVE RHODOMYRTONE STAPHYLOCOCCUS |
| title_short |
Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus |
| title_full |
Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus |
| title_fullStr |
Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus |
| title_full_unstemmed |
Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus |
| title_sort |
Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus |
| dc.creator.none.fl_str_mv |
Nguyen, Minh-Thu Saising, Jongkon Tribelli, Paula Maria Nega, Mulugeta Diene, Seydina M. François, Patrice Schrenzel, Jacques Spröer, Cathrin Bunk, Boyke Ebner, Patrick Hertlein, Tobias Kumari, Nimerta Härtner, Thomas Wistuba, Dorothee Voravuthikunchai, Supayang P. Mäder, Ulrike Ohlsen, Knut Götz, Friedrich |
| author |
Nguyen, Minh-Thu |
| author_facet |
Nguyen, Minh-Thu Saising, Jongkon Tribelli, Paula Maria Nega, Mulugeta Diene, Seydina M. François, Patrice Schrenzel, Jacques Spröer, Cathrin Bunk, Boyke Ebner, Patrick Hertlein, Tobias Kumari, Nimerta Härtner, Thomas Wistuba, Dorothee Voravuthikunchai, Supayang P. Mäder, Ulrike Ohlsen, Knut Götz, Friedrich |
| author_role |
author |
| author2 |
Saising, Jongkon Tribelli, Paula Maria Nega, Mulugeta Diene, Seydina M. François, Patrice Schrenzel, Jacques Spröer, Cathrin Bunk, Boyke Ebner, Patrick Hertlein, Tobias Kumari, Nimerta Härtner, Thomas Wistuba, Dorothee Voravuthikunchai, Supayang P. Mäder, Ulrike Ohlsen, Knut Götz, Friedrich |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
ANTIBIOTIC GRAM-POSITIVE BACTERIA MEMBRANE ACTIVE RHODOMYRTONE STAPHYLOCOCCUS |
| topic |
ANTIBIOTIC GRAM-POSITIVE BACTERIA MEMBRANE ACTIVE RHODOMYRTONE STAPHYLOCOCCUS |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
Rhodomyrtone (Rom) is an acylphloroglucinol antibiotic originally isolated from leaves of Rhodomyrtus tomentosa. Rom targets the bacterial membrane and is active against a wide range of Gram-positive bacteria but the exact mode of action remains obscure. Here we isolated and characterized a spontaneous Rom-resistant mutant from the model strain Staphylococcus aureus HG001 (RomR) to learn more about the resistance mechanism. We showed that Rom-resistance is based on a single point mutation in the coding region of farR [regulator of fatty acid (FA) resistance] that causes an amino acid change from Cys to Arg at position 116 in FarR, that affects FarR activity. Comparative transcriptome analysis revealed that mutated farR affects transcription of many genes in distinct pathways. FarR represses for example the expression of its own gene (farR), its flanking gene farE (effector of FA resistance), and other global regulators such as agr and sarA. All these genes were consequently upregulated in the RomR clone. Particularly the upregulation of agr and sarA leads to increased expression of virulence genes rendering the RomR clone more cytotoxic and more pathogenic in a mouse infection model. The Rom-resistance is largely due to the de-repression of farE. FarE is described as an efflux pump for linoleic and arachidonic acids. We observed an increased release of lipids in the RomR clone compared to its parental strain HG001. If farE is deleted in the RomR clone, or, if native farR is expressed in the RomR strain, the corresponding strains become hypersensitive to Rom. Overall, we show here that the high Rom-resistance is mediated by overexpression of farE in the RomR clone, that FarR is an important regulator, and that the point mutation in farR (RomR clone) makes the clone hyper-virulent. Fil: Nguyen, Minh-Thu. Eberhard Karls Universität Tübingen.; Alemania Fil: Saising, Jongkon. Eberhard Karls Universität Tübingen.; Alemania Fil: Tribelli, Paula Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Eberhard Karls Universität Tübingen.; Alemania Fil: Nega, Mulugeta. Eberhard Karls Universität Tübingen.; Alemania Fil: Diene, Seydina M.. Geneva University Hospitals; Suiza Fil: François, Patrice. Geneva University Hospitals; Suiza Fil: Schrenzel, Jacques. Geneva University Hospitals; Suiza Fil: Spröer, Cathrin. Leibniz Institute Dsmz-german Collection Of Microorgani; Alemania Fil: Bunk, Boyke. Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH; Alemania Fil: Ebner, Patrick. Eberhard Karls Universität Tübingen.; Alemania Fil: Hertlein, Tobias. University Of Würzburg; Alemania Fil: Kumari, Nimerta. Eberhard Karls Universität Tübingen.; Alemania Fil: Härtner, Thomas. Eberhard Karls Universität Tübingen.; Alemania Fil: Wistuba, Dorothee. Eberhard Karls Universität Tübingen.; Alemania Fil: Voravuthikunchai, Supayang P.. Prince Of Songkla University; Tailandia Fil: Mäder, Ulrike. University Medicine Greifswald; Alemania Fil: Ohlsen, Knut. University Of Würzburg; Alemania Fil: Götz, Friedrich. Eberhard Karls Universität Tübingen.; Alemania |
| description |
Rhodomyrtone (Rom) is an acylphloroglucinol antibiotic originally isolated from leaves of Rhodomyrtus tomentosa. Rom targets the bacterial membrane and is active against a wide range of Gram-positive bacteria but the exact mode of action remains obscure. Here we isolated and characterized a spontaneous Rom-resistant mutant from the model strain Staphylococcus aureus HG001 (RomR) to learn more about the resistance mechanism. We showed that Rom-resistance is based on a single point mutation in the coding region of farR [regulator of fatty acid (FA) resistance] that causes an amino acid change from Cys to Arg at position 116 in FarR, that affects FarR activity. Comparative transcriptome analysis revealed that mutated farR affects transcription of many genes in distinct pathways. FarR represses for example the expression of its own gene (farR), its flanking gene farE (effector of FA resistance), and other global regulators such as agr and sarA. All these genes were consequently upregulated in the RomR clone. Particularly the upregulation of agr and sarA leads to increased expression of virulence genes rendering the RomR clone more cytotoxic and more pathogenic in a mouse infection model. The Rom-resistance is largely due to the de-repression of farE. FarE is described as an efflux pump for linoleic and arachidonic acids. We observed an increased release of lipids in the RomR clone compared to its parental strain HG001. If farE is deleted in the RomR clone, or, if native farR is expressed in the RomR strain, the corresponding strains become hypersensitive to Rom. Overall, we show here that the high Rom-resistance is mediated by overexpression of farE in the RomR clone, that FarR is an important regulator, and that the point mutation in farR (RomR clone) makes the clone hyper-virulent. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019-05 |
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http://hdl.handle.net/11336/123548 Nguyen, Minh-Thu; Saising, Jongkon; Tribelli, Paula Maria; Nega, Mulugeta; Diene, Seydina M.; et al.; Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus; Frontiers Media S.A.; Frontiers in Microbiology; 10; MAY; 5-2019; 1-14 1664-302X CONICET Digital CONICET |
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http://hdl.handle.net/11336/123548 |
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Nguyen, Minh-Thu; Saising, Jongkon; Tribelli, Paula Maria; Nega, Mulugeta; Diene, Seydina M.; et al.; Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus; Frontiers Media S.A.; Frontiers in Microbiology; 10; MAY; 5-2019; 1-14 1664-302X CONICET Digital CONICET |
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