TY - JOUR
T1 - The two-component system WalKR provides an essential link between cell wall homeostasis and DNA replication in Staphylococcus aureus
AU - Sharkey, Liam K.R.
AU - Guerillot, Romain
AU - Walsh, Calum J.
AU - Turner, Adrianna M.
AU - Lee, Jean Y.H.
AU - Neville, Stephanie L.
AU - Klatt, Stephan
AU - Baines, Sarah L.
AU - Pidot, Sacha J.
AU - Rossello, Fernando J.
AU - Seemann, Torsten
AU - McWilliam, Hamish E.G.
AU - Cho, Ellie
AU - Carter, Glen P.
AU - Howden, Benjamin P.
AU - McDevitt, Christopher A.
AU - Hachani, Abderrahman
AU - Stinear, Timothy P.
AU - Monk, Ian R.
N1 - Funding Information:
We are grateful to the following colleague- for their advice, a-i-tance, and input into thiwork: Ju-tin Clarke, Charlie Higg-, Danielle Ingle, and Karinna Saxby. Funder DHAC | National Health and Medical Re-earch Council (NHMRC) DHAC | National Health and Medical Re-earch Council (NHMRC) Au-tralian Government Re-earch Training Program Scholar-hip DHAC | National Health and Medical Re-earch Council (NHMRC) Grant(s) GNT1145075 APP1105525 2003192 Author(s) Tor-ten Seemann Chri-topher A. McDevitt Timothy P. Stinear Ian R. Monk Timothy P. Stinear Adrianna M. Turner Hami-h E. G. McWilliam
Publisher Copyright:
Copyright © 2023 Sharkey et al.
PY - 2023/12
Y1 - 2023/12
N2 - Among the 16 two-component -y-tem- in the opportuni-tic human pathogen Staphylococcus aureus, only WalKR i- e-ential. Like the orthologou- -y-tem- in other Bacillota, S. aureus WalKR control- autoly-in- involved in peptidoglycan remodeling and i- therefore intimately involved in cell divi-ion. However, de-pite the importance of WalKR in S. aureus, the ba-i- for it- e-entiality i- not under-tood and the regulon i-poorly defined. Here, we defined a con-en-u- WalR DNA-binding motif and the direct WalKR regulon by u-ing functional genomic-, including chromatin immunoprecipitation -equencing, with a panel of i-ogenic walKR mutant- that had a -pectrum of altered activitie-. Con-i-tent with prior finding-, the direct regulon include- multiple autoly-in gene-. However, thi- work al-o revealed that WalR directly regulate- at lea-t five e-ential gene- involved in lipoteichoic acid -ynthe-i- (ltaS): tran-lation (rplK), DNA compaction (hup), initiation of DNA replication (dnaA, hup) and purine nucleotide metaboli-m (prs). Thu-, WalKR in S. aureus -erve- a- a polyfunctional regulator that contribute-to fundamental control over critical cell proce-e- by coordinately linking cell wall homeo-ta-i- with purine bio-ynthe-i-, protein bio-ynthe-i-, and DNA replication. Our finding- further addre- the e-entiality of thi- locu- and highlight the importance of WalKR a- a bona fide target for novel anti-taphylococcal therapeutic-.
AB - Among the 16 two-component -y-tem- in the opportuni-tic human pathogen Staphylococcus aureus, only WalKR i- e-ential. Like the orthologou- -y-tem- in other Bacillota, S. aureus WalKR control- autoly-in- involved in peptidoglycan remodeling and i- therefore intimately involved in cell divi-ion. However, de-pite the importance of WalKR in S. aureus, the ba-i- for it- e-entiality i- not under-tood and the regulon i-poorly defined. Here, we defined a con-en-u- WalR DNA-binding motif and the direct WalKR regulon by u-ing functional genomic-, including chromatin immunoprecipitation -equencing, with a panel of i-ogenic walKR mutant- that had a -pectrum of altered activitie-. Con-i-tent with prior finding-, the direct regulon include- multiple autoly-in gene-. However, thi- work al-o revealed that WalR directly regulate- at lea-t five e-ential gene- involved in lipoteichoic acid -ynthe-i- (ltaS): tran-lation (rplK), DNA compaction (hup), initiation of DNA replication (dnaA, hup) and purine nucleotide metaboli-m (prs). Thu-, WalKR in S. aureus -erve- a- a polyfunctional regulator that contribute-to fundamental control over critical cell proce-e- by coordinately linking cell wall homeo-ta-i- with purine bio-ynthe-i-, protein bio-ynthe-i-, and DNA replication. Our finding- further addre- the e-entiality of thi- locu- and highlight the importance of WalKR a- a bona fide target for novel anti-taphylococcal therapeutic-.
KW - -plit lucifera-e
KW - ChIP-eq
KW - CRISPRi
KW - DNA compaction
KW - DNA replication
KW - e-ential gene-
KW - regulation of gene expre-ion
KW - RNA-eq
KW - Staphylococcus aureus
KW - two-component regulatory -y-tem-
KW - WalKR
KW - WalR
UR - http://www.scopus.com/inward/record.url?scp=85183107725&partnerID=8YFLogxK
U2 - 10.1128/mbio.02262-23
DO - 10.1128/mbio.02262-23
M3 - Article
C2 - 37850732
AN - SCOPUS:85183107725
SN - 2150-7511
VL - 14
JO - mBio
JF - mBio
IS - 6
ER -