Siderophores are small organic molecules that bind and transport iron. These natural products have applications in medicine, agriculture, and environmental sciences. Bacteria are prominent producers of siderophores, which are essential for scavenging iron from their environment. Like other specialized metabolites, siderophore production is encoded within Biosynthetic Gene Clusters (BGCs). Studying siderophore-encoding BGCs leads to understanding their distribution and evolution, which is valuable for scientific research and design of novel molecules with desired properties.
To investigate the distribution and evolution of siderophore biosynthesis within the bacterial kingdom, we created an extensive database of experimentally validated siderophore BGCs. In addition, we are examining siderophore transport systems and their evolution across bacterial species to explore their potential use in developing Trojan horse drugs. By exploiting these transport pathways, it may be possible to deliver antimicrobial agents selectively to pathogenic bacteria.
Using Hidden Markov models, we conducted a comprehensive search to identify all potential siderophore producers within the GTDB tree of bacteria. We then performed a phylogenetic analysis on core genes involved in the biosynthesis of iron-chelating moieties. By reconciling the gene trees with their corresponding species tree, we traced evolutionary events—such as gene duplication, gene loss, and horizontal gene transfer—that have shaped their current distribution.
Our findings suggest that hydroxamates are likely the most ancient chelator group, with at least three distinct origins, predominantly found in Pseudomonadota and Actinobacteriota. Catecholates, also rather ancient, likely have a single origin in Actinobacteriota, with transfers to Pseudomonadota and Firmicutes. In contrast, pyoverdines appear to be the most recent siderophore pathway, found exclusively in Pseudomonads. Preliminary analysis of siderophore transport systems reveals conserved mechanisms that may be adapted for targeted drug delivery.
These insights into the evolutionary history of siderophores provide a foundation for future research, including the development of feasible mix-and-match methods and the selection of optimal heterologous hosts. Furthermore, understanding siderophore transport systems could inform the design of novel therapeutic approaches to deliver antimicrobial agents selectively to pathogens via Trojan horse strategies.