Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus
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 spontane...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2019.01157/full |
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| author | Minh-Thu Nguyen Minh-Thu Nguyen Jongkon Saising Jongkon Saising Paula Maria Tribelli Paula Maria Tribelli Mulugeta Nega Seydina M. Diene Patrice François Jacques Schrenzel Cathrin Spröer Boyke Bunk Patrick Ebner Tobias Hertlein Nimerta Kumari Thomas Härtner Dorothee Wistuba Supayang P. Voravuthikunchai Ulrike Mäder Knut Ohlsen Friedrich Götz |
| author_facet | Minh-Thu Nguyen Minh-Thu Nguyen Jongkon Saising Jongkon Saising Paula Maria Tribelli Paula Maria Tribelli Mulugeta Nega Seydina M. Diene Patrice François Jacques Schrenzel Cathrin Spröer Boyke Bunk Patrick Ebner Tobias Hertlein Nimerta Kumari Thomas Härtner Dorothee Wistuba Supayang P. Voravuthikunchai Ulrike Mäder Knut Ohlsen Friedrich Götz |
| author_sort | Minh-Thu Nguyen |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T21:36:14Z |
| format | Article |
| id | doaj.art-32bb6ed2199d4648b0e2e3b0876a60d8 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-13T21:36:14Z |
| publishDate | 2019-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-32bb6ed2199d4648b0e2e3b0876a60d82022-12-21T23:30:40ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2019-05-011010.3389/fmicb.2019.01157 448908Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureusMinh-Thu Nguyen0Minh-Thu Nguyen1Jongkon Saising2Jongkon Saising3Paula Maria Tribelli4Paula Maria Tribelli5Mulugeta Nega6Seydina M. Diene7Patrice François8Jacques Schrenzel9Cathrin Spröer10Boyke Bunk11Patrick Ebner12Tobias Hertlein13Nimerta Kumari14Thomas Härtner15Dorothee Wistuba16Supayang P. Voravuthikunchai17Ulrike Mäder18Knut Ohlsen19Friedrich Götz20Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, GermanyFederal Regulatory Agency for Vaccines and Biomedicines, Paul Ehrlich Institute, Langen, GermanyMicrobial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, GermanySchool of Health Science, Mae Fah Luang University, Chiang Rai, ThailandMicrobial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, GermanyDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales – Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, ArgentinaMicrobial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, GermanyGenomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, Geneva, SwitzerlandGenomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, Geneva, SwitzerlandGenomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, Geneva, SwitzerlandLeibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, GermanyLeibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, GermanyMicrobial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, GermanyInstitute of Molecular Infection Biology, University of Würzburg, Würzburg, GermanyMicrobial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, GermanyMicrobiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, GermanyInstitute for Organic Chemistry, University of Tübingen, Tübingen, Germany0Department of Microbiology, Natural Product Centre of Excellence, Prince of Songkla University, Hat Yai, Thailand1Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, GermanyInstitute of Molecular Infection Biology, University of Würzburg, Würzburg, GermanyMicrobial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, Tübingen, GermanyRhodomyrtone (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.https://www.frontiersin.org/article/10.3389/fmicb.2019.01157/fullantibioticGram-positive bacteriarhodomyrtoneStaphylococcusmembrane active |
| spellingShingle | Minh-Thu Nguyen Minh-Thu Nguyen Jongkon Saising Jongkon Saising Paula Maria Tribelli Paula Maria Tribelli Mulugeta Nega Seydina M. Diene Patrice François Jacques Schrenzel Cathrin Spröer Boyke Bunk Patrick Ebner Tobias Hertlein Nimerta Kumari Thomas Härtner Dorothee Wistuba Supayang P. Voravuthikunchai Ulrike Mäder Knut Ohlsen Friedrich Götz Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus Frontiers in Microbiology antibiotic Gram-positive bacteria rhodomyrtone Staphylococcus membrane active |
| title | 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_short | 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 |
| topic | antibiotic Gram-positive bacteria rhodomyrtone Staphylococcus membrane active |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2019.01157/full |
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