Mechanistic Insights into Wall Teichoic Acid Ligation and Regulation of Cytotoxicity in Staphylococcus aureus

Abstract

Staphylococcus aureus imposes a significant clinical burden, highlighting the need for novel treatment approaches. To cause severe infections, S. aureus employs a diverse arsenal of pathogenic mechanisms, including resistance to host antimicrobial factors and cytotoxicity. Bacterial factors involved in these processes are ideal targets for alternatives to, or adjuvants for antibiotics which disrupt the virulence potential of S. aureus. A genome wide association study identified TcaA as a key factor associated with serum resistance, potentially through an involvement in wall teichoic acid (WTA) ligation. Here, we characterised the transcriptional regulation of TcaA in response to host antimicrobial factors using a combination of GFP reporter assays and RT-qPCR. Furthermore, we utilised a co-immunoprecipitation and bacterial two-hybrid assays to identify interactions between TcaA and proteins involved in latestage WTA biosynthesis and penicillin binding proteins, supporting a role for this protein in WTA ligation. Additionally, we characterised the two-component system response regulator, PhoP as a novel regulator of cytotoxicity in S. aureus. We found that unphosphorylated PhoP is a strong activator of RNAIII and psmα1-4 expression in high-phosphate media, independently of changes in agrA expression. This presents a novel role for unphosphorylated response regulators, where gene regulation occurs independently of the cognate histidine kinase. Interestingly, signal activation in low-phosphate environments, causes phosphorylated PhoP to instead repress cytotoxicity. Both mechanistic findings highlight how S. aureus adapts its pathogenicity in host environments and are potential targets for development of novel therapeutics.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Ruth C Massey (Supervisor)