The two-component regulator WalKR provides an essential link between cell wall homeostasis with DNA replication inStaphylococcus aureus

Abstract

AbstractAmong the 16 two-component systems (TCSs) in the opportunistic human pathogenStaphylococcus aureus, only WalKR is essential. Like orthologous systems in other Bacillota,S. aureusWalKR controls autolysins involved in peptidoglycan remodelling and is therefore intimately involved in cell division. However, despite the importance of WalKR inS. aureus, the basis for its essentiality is not understood and the regulon poorly defined. Here, we defined a consensus WalR DNA-binding motif and the direct WalKR regulon by using functional genomics, including ChIP-seq, with a panel of isogenicwalKRmutants that had a spectrum of altered activities. Consistent with prior findings, the direct regulon includes multiple autolysin genes. However, this work also revealed that WalR directly regulates at least five essential genes involved in lipoteichoic acid synthesis (ltaS); translation(rplK); DNA compaction (hup); initiation of DNA replication (dnaA, hup); and purine nucleotide metabolism (prs). Thus, WalKR inS. aureusserves as a polyfunctional regulator that contributes to fundamental control over critical cell processes by co-ordinately linking cell wall homeostasis with purine biosynthesis, protein biosynthesis, and DNA replication. Collectively, our findings address the essentiality of this locus and highlight the importance of WalKR as abona fidetarget for novel anti-staphylococcal therapeutics.