TY - JOUR
T1 - Revisiting the Role of VraTSR in Staphylococcus aureus Response to Cell Wall-Targeting Antibiotics
AU - Fernandes, Pedro B.
AU - Reed, Patricia
AU - Monteiro, João M.
AU - Pinho, Mariana G.
N1 - Funding Information:
We thank Terry Roemer (Merck) for the generous gift of CDFI and Sérgio Filipe (FCT-NOVA) for helpful discussions. From ITQB, we thank Nathalie Reichmann for the plasmid pCNX-pbp2TP and Ambre Jousselin and Helena Veiga for developing the PhoB assay. This study was funded by the European Research Council through grant ERC-2017-CoG-771709 (to M.G.P.), by national funds through FCT: Fundação para a Ciência Project MOSTMICRO- ITQB R&D Unit (UIDB/04612/2020, UIDP/04612/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020) (to ITQB-NOVA) and FCT fellowship SFRH/BD/119996/2016 (to P.B.F.). Fig. 3a was created using BioRender.
Publisher Copyright:
Copyright © 2022 Fernandes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
PY - 2022/8
Y1 - 2022/8
N2 - Exposure of Staphylococcus aureus to cell wall inhibitors leads to the activation of the VraTSR three-component sensory regulatory system. This system is composed of VraS, a membrane histidine kinase; VraR, its cognate response regulator, and VraT, a protein required for the full activity of VraTSR. The exact function of VraT remains mostly uncharacterized, although it has been proposed to detect the unknown stimulus sensed by the VraTSR system. Here, we elucidate the topology of VraT, showing that its C-terminal domain is extracellular. We also demonstrate that the signal sensed by VraTSR is not an intermediate in the peptidoglycan synthesis pathway, as previously suggested. Instead, the specific inhibition of the penicillin-binding protein (PBP)2 leads to strong activation of the system. IMPORTANCE The Gram-positive bacterial pathogen Staphylococcus aureus is currently the second most frequent cause of global deaths associated with antibiotic resistance. Its response to cell wall-targeting antibiotics requires the VraTSR three-component system, which senses cell wall damage. Here, we show that the signal sensed by VraTSR is not an intermediate in the peptidoglycan synthesis pathway, as previously suggested. Instead, the specific inhibition of the penicillin-binding protein (PBP)2, the major peptidoglycan synthase in S. aureus, leads to strong activation of the system. Identifying the exact cell wall damage signal is key to fully understanding the response of S. aureus to cell wall-targeting antibiotics.
AB - Exposure of Staphylococcus aureus to cell wall inhibitors leads to the activation of the VraTSR three-component sensory regulatory system. This system is composed of VraS, a membrane histidine kinase; VraR, its cognate response regulator, and VraT, a protein required for the full activity of VraTSR. The exact function of VraT remains mostly uncharacterized, although it has been proposed to detect the unknown stimulus sensed by the VraTSR system. Here, we elucidate the topology of VraT, showing that its C-terminal domain is extracellular. We also demonstrate that the signal sensed by VraTSR is not an intermediate in the peptidoglycan synthesis pathway, as previously suggested. Instead, the specific inhibition of the penicillin-binding protein (PBP)2 leads to strong activation of the system. IMPORTANCE The Gram-positive bacterial pathogen Staphylococcus aureus is currently the second most frequent cause of global deaths associated with antibiotic resistance. Its response to cell wall-targeting antibiotics requires the VraTSR three-component system, which senses cell wall damage. Here, we show that the signal sensed by VraTSR is not an intermediate in the peptidoglycan synthesis pathway, as previously suggested. Instead, the specific inhibition of the penicillin-binding protein (PBP)2, the major peptidoglycan synthase in S. aureus, leads to strong activation of the system. Identifying the exact cell wall damage signal is key to fully understanding the response of S. aureus to cell wall-targeting antibiotics.
KW - antibiotic resistance
KW - peptidoglycan synthesis
KW - Staphylococcus aureus
KW - two-component system
UR - http://www.scopus.com/inward/record.url?scp=85136908495&partnerID=8YFLogxK
U2 - 10.1128/jb.00162-22
DO - 10.1128/jb.00162-22
M3 - Article
C2 - 35862765
AN - SCOPUS:85136908495
SN - 0021-9193
VL - 204
JO - Journal of Bacteriology
JF - Journal of Bacteriology
IS - 8
ER -