Analysis of the small RNA transcriptional response in multidrug-resistant Staphylococcus aureus after antimicrobial exposure

Benjamin Peter Howden, Marie Beaume, Paul Francis Harrison, David Hernandez, Jacques Schrenzel, Torsten Seemann, Patrice Francois, Timothy Paul Stinear

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Abstract

The critical role of non-coding small RNAs (sRNAs) in the bacterial response to changing conditions is increasingly recognized. However, a specific role for sRNAs during antibiotic exposure has not been investigated in S. aureus. Here, we used RNAseq to examine the sRNA response of the multiresistant ST239 S. aureus after exposure to four antibiotics (vancomycin, linezolid, ceftobiprole, and tigecycline) representing the major classes of antimicrobials used to treat methicillin-resistant S. aureus (MRSA) infections. We identified 409 potential sRNAs and then compared global sRNA and mRNA expression profiles at 2 and 6 hours, without antibiotic exposure, and after exposure to each antibiotic, for a vancomycin-susceptible (JKD6009) and a vancomycin-intermediate (JKD6008) strain. Exploration of this dataset by multivariate analysis using a novel implementation of non-negative matrix factorization (NMF) revealed very different responses for mRNA and sRNA. Where mRNA responses clustered with strain or growth phase conditions, the sRNA responses were predominantly linked to antibiotic exposure, including sRNA responses that were specific for particular antibiotics. A remarkable feature of the antimicrobial response was the prominence of antisense sRNAs to genes encoding proteins involved in protein synthesis and ribosomal function. This study has defined a large sRNA repertoire in epidemic ST239 MRSA, and shown for the first time that a subset of sRNAs are part of a coordinated transcriptional response to specific antimicrobial exposures in S. aureus. These data provides a framework for interrogating the role of staphylococcal sRNAs in antimicrobial resistance and exploring new avenues for sRNA-based antimicrobial therapies.
Original languageEnglish
Pages (from-to)3864 - 3874
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume57
Issue number8
DOIs
Publication statusPublished - 2013

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