Copper homeostasis networks in pseudomonas aeruginosa and the organocopper metabolite fluopsin C

Abstract Copper is an essential redox-active trace element that serves as a catalytic cofactor in many bacterial enzymes; however, excess intracellular copper is highly cytotoxic due to mismetallation of metalloproteins and copper-driven redox cycling that promotes reactive oxygen species generation through Fenton-like chemistry. To prevent these destructive effects, bacteria maintain near-zero levels of free cytosolic copper through tightly coordinated copper homeostasis networks. This review summarizes current understanding of bacterial copper stress physiology with a focus on the exceptionally copper-tolerant opportunistic pathogen Pseudomonas aeruginosa . This organism deploys a multilayered detoxification strategy that includes periplasmic copper surveillance and export mediated by the CopRS–PcoBA system, as well as highly sensitive cytoplasmic copper sensing that activates CueR-regulated efflux modules. A distinctive feature of the P. aeruginosa copper homeostasis network is the biosynthesis of the organometallic copper complex fluopsin C via a copper-responsive biosynthetic operon and its subsequent export through a dedicated efflux pump. This pathway supports a model in which fluopsin C functions as a copper-sequestering metabolite that stabilizes Cu(I), suppresses redox-mediated toxicity, and enables safe copper removal as a ligand-bound complex. Beyond its physiological role in copper detoxification, fluopsin C exhibits broad-spectrum antibacterial and antifungal activity and pronounced cytotoxicity toward mammalian tumor cell lines, consistent with a mechanism involving membrane disruption and ionophore-like copper shuttling. These properties suggest potential utility of fluopsin C as a metal-based, membrane-active antimicrobial in localized or formulation-controlled applications. Despite renewed interest in fluopsin C, optimization of its production remains limited, underscoring the need for future cultivation and bioprocess studies to improve yield and enable broader experimental and translational evaluation.