PR002636 (Project)

Description:Methicillin-resistant Staphylococcus aureus (MRSA) is a significant public health threat due to its extensive antimicrobial resistance and immune evasion capabilities, necessitating alternative therapeutic strategies. Disruption of bacterial metal ion homeostasis, a process already leveraged by host nutritional immunity, represents a promising approach. The zinc (Zn) ionophore PBT2 exhibits antibacterial activity and can resurrect the efficacy of conventional antibiotics. Here, we use PBT2 and Zn (PZ) to study the cellular response to metal dysregulation in MRSA strain USA300, identifying new metal-dependent molecular vulnerabilities. Integrated transcriptomics, metabolomics, and molecular analyses revealed that PZ’s antibacterial and oxacillin-resensitisation action is driven by dual metal stress: intracellular Zn accumulation and manganese (Mn) depletion, which excess Mn mitigated. PZ disrupted central carbon metabolism at multiple key nodes, impairing glycolysis, the TCA cycle and respiration, leading to NADH and ATP depletion and compromised peptidoglycan biosynthesis. PZ also altered the metal-dependent oxidative stress response, causing superoxide accumulation. This work presents a targetable interplay between bacterial metal ion homeostasis, central metabolism, and beta-lactam resistance. Uncovering how PBT2 subverts MRSA’s adaptive responses to host-imposed stresses contributes to our understanding of host-pathogen interactions and offers a foundation for developing novel antimicrobials based on metal homeostasis disruption.