Bacteria require sufficient iron in order to survive. However, because of the low solubility of iron in abiotic environments and the toxicity of iron in many biological settings, iron is present at concentrations too low to support bacterial growth. Bacteria have adapted to this challenge by producing siderophores, molecules that bind tightly to iron, and specific ferric-siderophore uptake systems to acquire enough iron to survive. In the pathogenic setting, this presents an opportunity to challenge microbial growth by the development of tools that could inhibit siderophore biosynthesis. The goal of these experiments are to prevent pathogens from obtaining the iron that they need to survive.
The importance of iron acquisition has caused numerous systems to arise even within a single species. Nonetheless, many studies have demonstrated that a single siderophore can play the dominant role in the establishment of a bacterial infection. This suggests that inhibitors for siderophore biosynthetic enzymes may have the potential for limiting bacterial growth.
Our studies have focused primarily on pyoverdine and aerobactin.
Pyoverdine is a peptide siderophore that is produced by NRPS enzymes within the bacteria Pseudomonas aeruginosa. We have identified a protein, PvdQ, that catalyzes one of the final steps in pyoverdine biosynthesis. We determined the function of this protein, determined its three-dimensional structure, and additionally developed a biochemical screen (1,2) to find small molecules that could block its activity. These compounds were effective at limiting bacterial growth in low iron conditions.
Aerobactin is a siderophore that has been implicated as a virulence factor in hypervirulent Klebsiella pneumoniae. Currently we are developing a high throughput screening assay to identify possible inhibitors of aerobactin biosynthesis, and working to determine 3D structures of the four proteins directly responsible for aerobactin production.