Stopping Bacteria from Stealing Our Iron

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By Ada Hagan
@adahagan

As we discussed last time, bacteria that infect the human body face a major challenge, iron, which is essential for bacterial growth, is hard to obtain from human tissues.  Many pathogenic bacteria solve this problem by deploying “stealth siderophores,” which steal iron from human iron-binding proteins while evading our defenses. In the battle between humans and pathogenic bacteria, our best weapons—antibiotics—are being weakened by widespread resistance. Is there a way to use bacteria’s need for iron against them?

Researchers have pursued the answer to this question since siderophores were discovered.

Needle in a haystack

In addition to siderophores, bacteria make other small molecules, called “natural products,” to accomplish functions outside of the cell (such as killing competing bacteria). David Sherman, a researcher at the University of Michigan, explores the vast world of natural products and searches for molecules with antimicrobial properties. One potentially vulnerable spot in pathogens’ iron-scavenging process is the assembly of the siderophore from smaller components. Sherman’s team tested nearly 20,000 natural products for their ability to inhibit enzymes that build siderophores in two dangerous pathogenic bacteria, Staphylococcus aureus and Bacillus anthracis. Two small molecules identified in this screen, baulamycins A and B, do just that and are potential weapons in the war against siderophores and infections.

Instead of looking for a needle in the haystack, other researchers take a different approach and create the needle. Here, researchers take the information that research has supplied about siderophore assembly to design and create small molecules that interfere with bacterial enzymes. This strategy has been used to jam up the living machinery of siderophore synthesis in Yersinia pestis and Mycobacterium tuberculosis.

Trojan horses

Bacteria often resist antibiotics by either pumping them out of the bacterial cell as fast as they get in or keeping them from getting in at all. To counter these strategies, researchers have attempted to disguise antibiotics with siderophores, creating sideromycins. By attaching the antibiotic to the needed siderophore, researchers have devised a microbial equivalent of the Trojan Horse.

Gathering iron via siderophores is a costly process, so many strains of bacteria poach siderophores made by other bacteria, even if they make their own. This allows researchers to pair a single siderophore with an antibiotic to target different types of bacteria based on the combination used. The trick with this strategy, however, is to know how each bacterial strain processes a particular siderophore.

For instance, Escherichia coli makes the siderophore enterobactin and can use the siderophore ferrichrome. However, E.coli removes iron from the two siderophores differently, breaking enterobactin apart but leaving ferrichrome intact and pumping it back out into the environment. This means that attaching an antibiotic to ferrichrome may not be any more effective against E. coli than using the antibiotic by itself, since it won’t stay inside the bacterial cell for very long. Attaching the same antibiotic to enterobactin, however, may cause it to accumulate in the cell more than if it were on its own, making the antibiotic more potent.

Vaccination

Of the more than 500 different siderophores in the microbial universe, each is recognized by a dedicated receptor protein for import into bacterial cells. So, while bacteria may poach siderophores made by a different bacterial species, they still must make the specific receptor for each siderophore that they use. These receptors, which protrude from the surface of the bacterial cell, are accessible by antibodies, a fact that has inspired researchers to attempt a different strategy: vaccination. Certain siderophores, typically the stealth siderophores, are used by pathogens but not by nonpathogenic bacteria like those in your gut microbiome. Perhaps those siderophores (or proteins involved in their use) can be used to target pathogens while leaving their friendly cousins in peace.

Harry Mobley’s lab at the University of Michigan has targeted the receptors for one stealth siderophore to vaccinate mice against urinary tract infections by pathogenic E. coli. By generating an immune response, the infection can be prevented from occurring in the first place, avoiding the need for antibiotics (or sideromycins).

If one or more of these research strategies pay off, the siderophore—a secret weapon for causing infections—may become the key to bacteria’s defeat.

This article originally appeared as a blog post on MiSciWriters.

Spinach and Siderophores—Ada Hagan is a graduate student in the Department of Microbiology and Immunology at the University of Michigan. Her doctoral research focuses on the methods that the bacterial pathogen Bacillus anthracis uses to gather iron during infections. Ada is also an advocate for science communication by scientists. She is a cofounder of the graduate student science writing blog MiSciWriters.com and a regular contributor to the American Society for Microbiology Microbial Sciences blog. You can follow her on Twitter @adahagan for more about microbiology, science communication, and life as a grad student mom.

References

Mislin, G. L. A., and Schalk, I. J. (2016). Siderophore-dependent iron uptake systems as gates for antibiotic Trojan horse strategies against Pseudomonas aeruginosa. Metallomics, 6, 408-420. DOI:10.1039/C3MT00359K.

Somu, R. V., Boshoff, H., Qiao, C., Bennett, E. M., Barry III, C. E., and, Aldrich, C. C. (2006). Rationally designed nucleoside antibiotics that inhibit siderophore biosynthesis of Mycobacterium tuberculosis. Journal of Medicinal Chemistry, 49 (1), 31-34 DOI: 10.1021/jm051060o.

Tripathi, A., Schofield, M. M., Chlipala, G. E., Schultz, P. J., Yim, I., Newmister, S. A., Nusca, T. D., Scaglione, J. B., Hanna, P. C., Tamayo-Castillo, G., and Sherman, D. H. (2014). Baulamycins A and B, Broad-Spectrum Antibiotics Identified as Inhibitors of Siderophore Biosynthesis in Staphylococcus aureus and Bacillus anthracis. Journal of the American Chemical Society, , 136 (4), 1579-1586 DOI: 10.1021/ja4115924.

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