Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus

Minh-Thu Nguyen (1, 2) , Jongkon Saising (1, 3) , Paula Maria Tribelli (1, 4) , Mulugeta Nega (1) , Seydina Diene (5) , Patrice François (5) , Jacques Schrenzel (5) , Cathrin Spröer (6) , Boyke Bunk (6) , Patrick Ebner (1) , Tobias Hertlein (7) , Nimerta Kumari (1) , Thomas Härtner (8) , Dorothee Wistuba (8) , Supayang Voravuthikunchai (9) , Ulrike Mäder (10) , Knut Ohlsen (7) , Friedrich Götz (1)

1 Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen
2 EPI - Paul-Ehrlich-Institute - Federal Institute for Vaccines and Biomedicines
3 MFU - Mae Fah Luang University [Thaïlande]
4 UBA - Universidad de Buenos Aires [Buenos Aires]
5 HUG - Geneva University Hospital
6 DSMZ - Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH / Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures
7 University of Würzburg
8 University of Tübingen
9 PSU - Prince of Songkla University
10 Universität Greifswald - University of Greifswald

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 (Rom R) 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 Rom R clone. Particularly the upregulation of agr and sarA leads to increased expression of virulence genes rendering the Rom R 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 Rom R clone compared to its parental strain HG001. If farE is deleted in the Rom R clone, or, if native farR is expressed in the Rom R strain, Frontiers in Microbiology | www.frontiersin.org 1 May 2019 | Volume 10 | Article 1157 Nguyen et al. Rhodomyrtone (ROM) Resistance in S. aureus the corresponding strains become hypersensitive to Rom. Overall, we show here that the high Rom-resistance is mediated by overexpression of farE in the Rom R clone, that FarR is an important regulator, and that the point mutation in farR (Rom R clone) makes the clone hyper-virulent.

Mots clés: antibiotic; Gram-positive bacteria; rhodomyrtone; Staphylococcus; membrane active

Domaines: Bactériologie; Virologie; Parasitologie; Cardiologie et système cardiovasculaire; Maladies émergentes; Maladies infectieuses

Minh-Thu Nguyen, Jongkon Saising, Paula Maria Tribelli, Mulugeta Nega, Seydina Diene, et al.. Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus. Frontiers in Microbiology, 2019, 10, ⟨10.3389/fmicb.2019.01157⟩. ⟨hal-02263616⟩