RNase III-CLASH of multi-drug resistant Staphylococcus aureus reveals a regulatory mRNA 3′UTR required for intermediate vancomycin resistance

Daniel G. Mediati, Julia L. Wong, Wei Gao, Stuart McKellar, Chi Nam Ignatius Pang, Sylvania Wu, Winton Wu, Brandon Sy, Ian R. Monk, Joanna M. Biazik, Marc R. Wilkins, Benjamin P. Howden, Timothy P. Stinear, Sander Granneman and Jai J. Tree ()
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Daniel G. Mediati: University of New South Wales
Julia L. Wong: University of New South Wales
Wei Gao: Peter Doherty Institute, University of Melbourne
Stuart McKellar: University of Edinburgh
Chi Nam Ignatius Pang: University of New South Wales
Sylvania Wu: University of New South Wales
Winton Wu: University of New South Wales
Brandon Sy: University of New South Wales
Ian R. Monk: Peter Doherty Institute, University of Melbourne
Joanna M. Biazik: University of New South Wales
Marc R. Wilkins: University of New South Wales
Benjamin P. Howden: Peter Doherty Institute, University of Melbourne
Timothy P. Stinear: Peter Doherty Institute, University of Melbourne
Sander Granneman: University of Edinburgh
Jai J. Tree: University of New South Wales

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Treatment of methicillin-resistant Staphylococcus aureus infections is dependent on the efficacy of last-line antibiotics including vancomycin. Treatment failure is commonly linked to isolates with intermediate vancomycin resistance (termed VISA). These isolates have accumulated point mutations that collectively reduce vancomycin sensitivity, often by thickening the cell wall. Changes in regulatory small RNA expression have been correlated with antibiotic stress in VISA isolates however the functions of most RNA regulators is unknown. Here we capture RNA–RNA interactions associated with RNase III using CLASH. RNase III-CLASH uncovers hundreds of novel RNA–RNA interactions in vivo allowing functional characterisation of many sRNAs for the first time. Surprisingly, many mRNA–mRNA interactions are recovered and we find that an mRNA encoding a long 3′ untranslated region (UTR) (termed vigR 3′UTR) functions as a regulatory ‘hub’ within the RNA–RNA interaction network. We demonstrate that the vigR 3′UTR promotes expression of folD and the cell wall lytic transglycosylase isaA through direct mRNA–mRNA base-pairing. Deletion of the vigR 3′UTR re-sensitised VISA to glycopeptide treatment and both isaA and vigR 3′UTR deletions impact cell wall thickness. Our results demonstrate the utility of RNase III-CLASH and indicate that S. aureus uses mRNA-mRNA interactions to co-ordinate gene expression more widely than previously appreciated.

Date: 2022
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DOI: 10.1038/s41467-022-31177-8

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