Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus

  • Res Sq. 2026 Jan 12:rs.3.rs-8331258. doi: 10.21203/rs.3.rs-8331258/v1.
Raymond Poon  1  2 ,  Nidhi Satishkumar  1  2 ,  Wesley A Mosimann  3 ,  Vedangi Hayatnagarkar  1  2 ,  Vijay Hemmadi  1  2 ,  Skyler Kuhn  4 ,  Aditi Chatterjee  1  2 ,  Liam Worrall  3 ,  Nathan P Manes  5 ,  J Andrew N Alexander  3 ,  Justin Lack  4 ,  Henry F Chambers  6 ,  Aleksandra Nita-Lazar  5 ,  Natalie C J Strynadka  3 ,  Som S Chatterjee  1  2
Affiliations
  • 1. Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD, USA.
  • 2. Institute of Marine and Environmental Technology (IMET); Baltimore, MD, USA.
  • 3. Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
  • 4. Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD, USA.
  • 5. Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 6. Division of Infectious Disease, Department of Medicine, San Francisco General Hospital, San Francisco, CA, USA.
PMID: 41743328 DOI: 10.21203/rs.3.rs-8331258/v1
Abstract

Sensory induction of mecA expression plays a pivotal role in mediating broad-spectrum β-lactam resistance (BBR) of MRSA. In contemporary MRSA isolates, sensory induction of BBR originates at the membrane-localized BlaR1, which, upon detection of β-lactam drugs, triggers a signal transduction cascade that promotes mecA induction. We hereby showed that phosphorylation of BlaR1, mediated through the serine-threonine kinase, Stk1, stabilizes its membrane spanning state and localization, allowing for proper drug sensing and subsequent signal transduction events to occur, culminating in mecA-mediated BBR. Our results demonstrated that targeting Stk1 could potentiate synthetic lethality to β-lactams in the majority of naturally isolated strains of MRSA. We also presented the structural and kinetic basis for a Stk1-inhibitor complex that could enable rational design of Stk1 directed anti-MRSA therapeutics in the future. Our results reveal a unique and hitherto unknown role of the STK signaling pathway in Bacterial protein stabilization in the cytosolic membrane.

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