The 3′ UTR of vigR is required for virulence in Staphylococcus aureus and has expanded through STAR sequence repeat insertions
Daniel G. Mediati,
William Dan,
David Lalaouna,
Hue Dinh,
Alaska Pokhrel,
Keiran N. Rowell,
Katharine A. Michie,
Timothy P. Stinear,
Amy K. Cain,
Jai J. Tree
Affiliations
Daniel G. Mediati
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia; Australian Institute for Microbiology and Infection, University of Technology Sydney, Ultimo, NSW, Australia; Corresponding author
William Dan
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
David Lalaouna
Université de Strasbourg, CNRS, ARN UPR 9002, Strasbourg, France
Hue Dinh
School of Natural Sciences, ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney, NSW, Australia
Alaska Pokhrel
Australian Institute for Microbiology and Infection, University of Technology Sydney, Ultimo, NSW, Australia; School of Natural Sciences, ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney, NSW, Australia
Keiran N. Rowell
Structural Biology Facility, University of New South Wales, Sydney, NSW, Australia
Katharine A. Michie
Structural Biology Facility, University of New South Wales, Sydney, NSW, Australia
Timothy P. Stinear
Department of Microbiology and Immunology, Peter Doherty Institute, University of Melbourne, Melbourne, VIC, Australia
Amy K. Cain
School of Natural Sciences, ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney, NSW, Australia
Jai J. Tree
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia; Corresponding author
Summary: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are alarmingly common, and treatment is confined to last-line antibiotics. Vancomycin is the treatment of choice for MRSA bacteremia, and treatment failure is often associated with vancomycin-intermediate S. aureus isolates. The regulatory 3′ UTR of the vigR mRNA contributes to vancomycin tolerance and upregulates the autolysin IsaA. Using MS2-affinity purification coupled with RNA sequencing, we find that the vigR 3′ UTR also regulates dapE, a succinyl-diaminopimelate desuccinylase required for lysine and peptidoglycan synthesis, suggesting a broader role in controlling cell wall metabolism and vancomycin tolerance. Deletion of the 3′ UTR increased virulence, while the isaA mutant is completely attenuated in a wax moth larvae model. Sequence and structural analyses of vigR indicated that the 3′ UTR has expanded through the acquisition of Staphylococcus aureus repeat insertions that contribute sequence for the isaA interaction seed and may functionalize the 3′ UTR.
