High-pathogenicity island enhances NDM-5 activity and drives global spread of <i>Escherichia coli</i> ST410

The international high-risk clone Escherichia coli ST410 poses a serious threat to clinical therapy and public health. By analyzing 3,434 ST410 genomes, we observed a broad ecological and geographic distribution along with frequent acquisition of the carbapenem resistance gene blaNDM-5 and a yersiniabactin-encoding high-pathogenicity island (HPI). We found that blaNDM-5 and HPI co-occurred in the most successful subclades. Functional assays comparing the wild-type strain with its isogenic mutant demonstrated that HPI augments bacterial iron uptake, promotes growth under iron-limited conditions, and increases pathogenicity in a mouse infection model. HPI also increases intracellular zinc levels and boosts NDM-5 β-lactamase activity, thereby improving bacterial survival under imipenem exposure in vitro and in mice. These findings suggest that the successful dissemination of ST410 is propelled by a synergy between HPI-mediated metal acquisition and blaNDM-5, linking enhanced virulence with elevated antibiotic resistance. This study provides mechanistic insight into resistance-virulence co-evolution in an emerging bacterial lineage and illustrates how ecological selection imposed by metal limitation and antibiotic exposure can jointly shape the success of high-risk clones across diverse ecosystems.