The two-component system WalKR provides an essential link between cell wall homeostasis and DNA replication in Staphylococcus aureus

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-.