Staphylococcus aureus GpsB, Stk, and VraSR form a cell wall surveillance network to maintain cell envelope integrity and mediate antibiotic resistance
- 1Department of Molecular Biosciences, University of South Florida, Tampa, Florida, USA
Abstract
Antibiotic resistance is an alarming threat to public health worldwide. Specifically, drug-resistant Staphylococcus aureus remains a major contributor to global mortality. Therefore, in-depth understanding of antibiotic resistance mechanisms is urgently needed to inform alternative therapeutic strategies. We previously showed that GpsB is a critical regulator of cell wall synthesis in S. aureus. GpsB executes its regulatory role via protein-protein interactions. Yet, how GpsB function is modulated in this organism has remained unclear. Intriguingly, a prior proteomics report indicated that GpsB is phosphorylated at six different residues by the sole serine/threonine kinase Stk. Hence, we explored the physiological significance of GpsB phosphorylation. We identify three phosphosites that are each independently sufficient to drive GpsB phosphoregulation, which likely alters its partner preference. We find that cells lacking gpsB exhibit heightened fosfomycin sensitivity, and that this is exacerbated by stk deletion. Our findings reveal that GpsB collaborates with Stk and the VraSR cell wall stress response system to coordinate the demand-driven availability of cell wall precursors. Collectively, this report establishes GpsB as a pivotal peptidoglycan supply chain sentinel that together with Stk and VraSR forms an integrated cell wall stress monitoring network that maintains cell envelope homeostasis and aids in antibiotic resistance.
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BibTeX
@misc{mcknight2026staphylococcus,
title = {{Staphylococcus aureus GpsB, Stk, and VraSR form a cell wall surveillance network to maintain cell envelope integrity and mediate antibiotic resistance}},
author = {L. J. McKnight and O. Payne and A. King and J. Carroll and B. Boyer and A. Brown and L. R. Hammond and P. J. Eswara},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757784},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757784v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Staphylococcus aureus GpsB, Stk, and VraSR form a cell wall surveillance network to maintain cell envelope integrity and mediate antibiotic resistance
AU - L. J. McKnight
AU - O. Payne
AU - A. King
AU - J. Carroll
AU - B. Boyer
AU - A. Brown
AU - L. R. Hammond
AU - P. J. Eswara
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757784
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757784v1
AB - Antibiotic resistance is an alarming threat to public health worldwide. Specifically, drug-resistant Staphylococcus aureus remains a major contributor to global mortality. Therefore, in-depth understanding of antibiotic resistance mechanisms is urgently needed to inform alternative therapeutic strategies. We previously showed that GpsB is a critical regulator of cell wall synthesis in S. aureus. GpsB executes its regulatory role via protein-protein interactions. Yet, how GpsB function is modulated in this organism has remained unclear. Intriguingly, a prior proteomics report indicated that GpsB is phosphorylated at six different residues by the sole serine/threonine kinase Stk. Hence, we explored the physiological significance of GpsB phosphorylation. We identify three phosphosites that are each independently sufficient to drive GpsB phosphoregulation, which likely alters its partner preference. We find that cells lacking gpsB exhibit heightened fosfomycin sensitivity, and that this is exacerbated by stk deletion. Our findings reveal that GpsB collaborates with Stk and the VraSR cell wall stress response system to coordinate the demand-driven availability of cell wall precursors. Collectively, this report establishes GpsB as a pivotal peptidoglycan supply chain sentinel that together with Stk and VraSR forms an integrated cell wall stress monitoring network that maintains cell envelope homeostasis and aids in antibiotic resistance.
ER -