The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis.

Autor:	Xiong YQ; The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.; Department of Medicine, Division of Infectious Diseases, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA., Li Y; The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA., Goncheva MI; Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada., Elsayed AM; The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA., Zhu F; The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA., Li L; The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA., Abdelhady W; The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA., Flannagan RS; Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada., Yeaman MR; The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.; Department of Medicine, Division of Infectious Diseases, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.; Department of Medicine, Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA., Bayer AS; The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.; Department of Medicine, Division of Infectious Diseases, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA., Heinrichs DE; Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	The Journal of infectious diseases [J Infect Dis] 2024 Jun 14; Vol. 229 (6), pp. 1648-1657.
DOI:	10.1093/infdis/jiad577
Abstrakt:	Background: Staphylococcus aureus is the most common cause of life-threatening endovascular infections, including infective endocarditis (IE). These infections, especially when caused by methicillin-resistant strains (MRSA), feature limited therapeutic options and high morbidity and mortality rates. Methods: Herein, we investigated the role of the purine biosynthesis repressor, PurR, in virulence factor expression and vancomycin (VAN) treatment outcomes in experimental IE due to MRSA. Results: The PurR-mediated repression of purine biosynthesis was confirmed by enhanced purF expression and production of an intermediate purine metabolite in purR mutant strain. In addition, enhanced expression of the transcriptional regulators, sigB and sarA, and their key downstream virulence genes (eg, fnbA, and hla) was demonstrated in the purR mutant in vitro and within infected cardiac vegetations. Furthermore, purR deficiency enhanced fnbA/fnbB transcription, translating to increased fibronectin adhesion versus the wild type and purR-complemented strains. Notably, the purR mutant was refractory to significant reduction in target tissues MRSA burden following VAN treatment in the IE model. Conclusions: These findings suggest that the purine biosynthetic pathway intersects the coordination of virulence factor expression and in vivo persistence during VAN treatment, and may represent an avenue for novel antimicrobial development targeting MRSA. Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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