Role of Purine Biosynthesis in Persistent Methicillin-Resistant Staphylococcus aureus (MRSA) Infection

Role of Purine Biosynthesis in Persistent Methicillin-Resistant Staphylococcus aureus (MRSA)... Abstract Persistent MRSA bacteremia (PB) represents an important subset of S. aureus endovascular infections. In this study, we investigated potential genetic mechanisms underlying the persistent outcomes. Compared to resolving bacteremia (RB) isolates (negative blood cultures within 2-4 days of therapy), PB strains (positive blood cultures after ≥ 7 days of therapy) had significantly: i) earlier-onset activation of key virulence regulons and structural genes (e.g., sigB, sarA, sae and cap5); ii) higher expression of purine biosynthesis genes (e.g., purF); and iii) faster growth rates, with earlier entrance into stationary phase. Importantly, an isogenic strain-set featuring a wild-type MRSA isolate, its purF-mutant and -complemented strain, and use of strategic purine biosynthesis inhibitors implicated a causal relationship between purine biosynthesis and the in vivo persistent outcomes. These observations suggest that purine biosynthesis plays a key role in the PB outcome, and may represent a new target for enhanced efficacy in treating life-threatening MRSA infections. MRSA, purine biosynthesis, persistent endovascular infection © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Infectious Diseases Oxford University Press

Role of Purine Biosynthesis in Persistent Methicillin-Resistant Staphylococcus aureus (MRSA) Infection

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
ISSN
0022-1899
eISSN
1537-6613
D.O.I.
10.1093/infdis/jiy340
Publisher site
See Article on Publisher Site

Abstract

Abstract Persistent MRSA bacteremia (PB) represents an important subset of S. aureus endovascular infections. In this study, we investigated potential genetic mechanisms underlying the persistent outcomes. Compared to resolving bacteremia (RB) isolates (negative blood cultures within 2-4 days of therapy), PB strains (positive blood cultures after ≥ 7 days of therapy) had significantly: i) earlier-onset activation of key virulence regulons and structural genes (e.g., sigB, sarA, sae and cap5); ii) higher expression of purine biosynthesis genes (e.g., purF); and iii) faster growth rates, with earlier entrance into stationary phase. Importantly, an isogenic strain-set featuring a wild-type MRSA isolate, its purF-mutant and -complemented strain, and use of strategic purine biosynthesis inhibitors implicated a causal relationship between purine biosynthesis and the in vivo persistent outcomes. These observations suggest that purine biosynthesis plays a key role in the PB outcome, and may represent a new target for enhanced efficacy in treating life-threatening MRSA infections. MRSA, purine biosynthesis, persistent endovascular infection © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

The Journal of Infectious DiseasesOxford University Press

Published: Jun 2, 2018

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