Peer-reviewedCC BY-NC-NDNature communications
Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus.
9 affiliations
- 1Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD, USA.
- 2Institute of Marine and Environmental Technology (IMET), Baltimore, MD, USA.
- 3Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
- 4Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
- 5University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
- 6Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
- 7Division of Infectious Disease, Department of Medicine, San Francisco General Hospital, San Francisco, CA, USA.
- 8Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD, USA. [email protected].
- 9Institute of Marine and Environmental Technology (IMET), Baltimore, MD, USA. [email protected].
Abstract
Sensory induction of mecA expression plays a pivotal role in mediating broad-spectrum β-lactam resistance of MRSA. In contemporary MRSA isolates, sensory induction of β-lactam resistance originates at the membrane-associated BlaR1, which, upon detection of β-lactam drugs, triggers a signal transduction cascade that promotes mecA induction. We hereby show that phosphorylation of BlaR1, mediated through the serine-threonine kinase, Stk1, stabilizes its membrane-spanning state and retention, allowing for proper drug sensing and subsequent signal transduction events to occur, culminating in mecA-mediated β-lactam resistance. Our results demonstrate that targeting Stk1 can potentiate synthetic lethality to β-lactams in the majority of naturally isolated strains of MRSA. We additionally present the structural and kinetic basis for a Stk1-inhibitor complex that can enable rational design of Stk1-directed anti-MRSA therapeutics in the future. Our results reveal a novel role of the STK signaling pathway in bacterial protein stabilization in the cytosolic membrane.
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BibTeX
@article{poon2026stk1,
title = {{Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus.}},
author = {Raymond Poon and Nidhi Satishkumar and Wesley A Mosimann and Vedangi D Hayatnagarkar and Swagata Bose and Vijay Hemmadi and Skyler Kuhn and Aditi Chatterjee and Liam Worrall and Nathan P Manes and J Andrew N Alexander and Justin Lack and Henry F Chambers and Aleksandra Nita-Lazar and Natalie C J Strynadka and Som S Chatterjee},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77668-w},
url = {https://europepmc.org/article/MED/42894009},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus.
AU - Raymond Poon
AU - Nidhi Satishkumar
AU - Wesley A Mosimann
AU - Vedangi D Hayatnagarkar
AU - Swagata Bose
AU - Vijay Hemmadi
AU - Skyler Kuhn
AU - Aditi Chatterjee
AU - Liam Worrall
AU - Nathan P Manes
AU - J Andrew N Alexander
AU - Justin Lack
AU - Henry F Chambers
AU - Aleksandra Nita-Lazar
AU - Natalie C J Strynadka
AU - Som S Chatterjee
PY - 2026
DA - 2026/09/16
JO - Nature communications
DO - 10.1038/s41467-026-77668-w
UR - https://europepmc.org/article/MED/42894009
AB - Sensory induction of mecA expression plays a pivotal role in mediating broad-spectrum β-lactam resistance of MRSA. In contemporary MRSA isolates, sensory induction of β-lactam resistance originates at the membrane-associated BlaR1, which, upon detection of β-lactam drugs, triggers a signal transduction cascade that promotes mecA induction. We hereby show that phosphorylation of BlaR1, mediated through the serine-threonine kinase, Stk1, stabilizes its membrane-spanning state and retention, allowing for proper drug sensing and subsequent signal transduction events to occur, culminating in mecA-mediated β-lactam resistance. Our results demonstrate that targeting Stk1 can potentiate synthetic lethality to β-lactams in the majority of naturally isolated strains of MRSA. We additionally present the structural and kinetic basis for a Stk1-inhibitor complex that can enable rational design of Stk1-directed anti-MRSA therapeutics in the future. Our results reveal a novel role of the STK signaling pathway in bacterial protein stabilization in the cytosolic membrane.
SN - 2041-1723
ER -