Navigating the copper highway: bacterial strategies for cytoplasmic import

Copper is an essential yet potentially toxic metal, and bacteria have evolved intricate systems to manage its uptake, trafficking, and utilization. This review summarizes recent advances in our understanding of bacterial copper acquisition. Copper is transported across the outer membrane via porins and TonB-dependent transporters (TBDTs), and received by periplasmic chaperones such as CopC, PmoF, and YcnI. These components have been structurally and functionally characterized. By contrast, molecular level understanding of copper transport across the gram-negative bacterial inner membrane via systems like P_1B-ATPases, major facilitator superfamily (MFS) transporters, and CopD family proteins remains limited. We highlight this critical gap and identify cytoplasmic copper import as a promising frontier for in vitro and structural studies. Given the central role of copper homeostasis in bacterial survival and pathogenesis, these import systems represent compelling targets for antibiotic development.