Bacterial competition mediated by siderophore production among the human nasal microbiota
Authors: Stubbendieck Reed M. , May Daniel S. , Chevrette Marc G. , Temkin Mia I. , Wendt-Pienkowski Evelyn , Cagnazzo Julian , Carlson Caitlin M. , Gern James E. , Currie Cameron R. 
Published: October 2018

ABSTRACTResources available in the human nasal cavity are limited. Therefore, to successfully colonize the nasal cavity, bacteria must compete for scarce nutrients. Competition may occur directly through interference (e.g., antibiotics) or indirectly by nutrient sequestration. To investigate the nature of nasal bacterial competition, we performed co-culture inhibition assays between nasal Actinobacteria andStaphylococcusspp. We found thatStaphylococcus epidermidisisolates were sensitive to growth inhibition by Actinobacteria butStaphylococcus aureusisolates were resistant to inhibition. Among Actinobacteria, we observed thatCorynebacteriumspp. were variable in their ability to inhibitS. epidermidis.We sequenced the genomes of tenCorynebacteriumspp. isolates, including threeCorynebacterium propinquumthat strongly inhibitedS. epidermidisand seven otherCorynebacteriumspp. isolates that only weakly inhibitedS. epidermidis.Using a comparative genomics approach, we found that theC. propinquumgenomes were enriched in genes for iron acquisition and encoded a biosynthetic gene cluster (BGC) for siderophore production, absent in the non-inhibitoryCorynebacteriumspp. genomes. Using a chromeazurol S assay, we confirmed thatC. propinquumproduced siderophores. We demonstrated that iron supplementation rescuedS. epidermidisfrom inhibition byC. propinquum, suggesting that inhibition was due to iron restriction through siderophore production. Using comparative metabolomics, we identified the siderophore produced byC. propinquumas dehydroxynocardamine. Finally, we confirmed that the dehydroxynocardamine BGC is expressedin vivoby analyzing human nasal metatranscriptomes from the NIH Human Microbiome Project.Together, our results suggest that bacteria produce siderophores to compete for limited available iron in the nasal cavity and improve their fitness.IMPORTANCEWithin the nasal cavity, interference competition through antimicrobial production is prevalent. For instance, nasalStaphylococcusspp. strains can inhibit the growth of other bacteria through the production of nonribosomal peptides and ribosomally synthesized and post-translationally modified peptides. In contrast, bacteria engaging in exploitation competition modify the external environment to prevent competitors from growing, usually by depleting access to essential nutrients. As the nasal cavity is a nutrient limited environment, we hypothesized that exploitation competition occurs in this system. We determined thatCorynebacterium propinquumproduces an iron-chelating siderophore and is able to use this molecule to sequester iron and inhibit the growth ofStaphylococcus epidermidis.Further, we found that the genes required for siderophore production are expressedin vivo.Thus, though siderophore production by bacteria is often considered a virulence trait, our work indicates that bacteria may produce siderophores to compete for limited iron in the human nasal cavity.