From antibiotic to chalkophore: the biology and evolution of SF2768 in <i>Streptomyces</i>

Copper availability is tightly regulated in microbial environments, yet the diversity and evolutionary origins of copper-chelating metabolites remain poorly understood. SF2768, a diisonitrile compound from Streptomyces, functions both as a broad-spectrum antibiotic and as a highly specific secreted copper chelator (chalkophore) that binds copper with a 1:2 stoichiometry. Its biosynthesis depends on an NRPS encoded in the sfa gene cluster, which also includes an ABC transporter required for uptake of the Cu-SF2768 complex. A phylogenetic survey revealed that while some Streptomyces species retain both biosynthetic and uptake genes, others possess only the uptake system, indicating interspecies utilization of the metabolite. These findings suggest that SF2768 may have originated as an antibiotic that kills competing microbes by inducing copper starvation, and was later co-opted by certain Streptomyces as a copper acquisition system. The distribution of sfa genes illustrates how novel metabolic functions can emerge from secondary metabolism and become ecologically embedded. SF2768 provides a model for understanding the evolutionary transition of secondary metabolites from competitive weapons to cooperative or utilitarian factors within microbial communities.