The Berkeley Science Review: Articles

Double Trouble
Anthrax has two tricks for stealing iron (view PDF)
by Natasha Keith

From its ability to infect by inhalation to its explosive growth that causes host death in a mere three days, Bacillus anthracis, or anthrax, has a privileged place in the public consciousness as a potent bioterrorism agent. And since this speedy growth is one of the most dangerous aspects of infection, research that identifies central elements to anthrax’s life cycle is important. By asking the innocent-sounding question of how the bug gets its nutrients, researchers at UC Berkeley are hoping to target a key step of anthrax infection.

Bacteria, just like humans, need certain minerals to grow and thrive. One particularly important yet hard-to-get mineral is iron, which is used for a variety of energetic processes in the cell. In anthrax’s mammalian hosts, iron can be found either bound tightly to proteins like hemoglobin or as free-floating ions in solution. Although “free iron” is the easiest for bacteria to harvest, it is tightly regulated in the host to prevent a free lunch for invaders, as well as to prevent iron from forming ferociously reactive oxidants that damage cells. Only a very small and stable concentration of free iron is present in the blood at any given time.

Anthrax harvests this tiny amount of free iron in a manner also used by some other infamous bacterial strains, including Mycobacterium tuberculosis, Klebsiella pneumoniae and Yersinia pestis (the plague). Once in the circulatory system, the bacteria secrete iron-scavenging molecules called “siderophores” (Greek: sidero=iron, phore=carrier) that bind tightly to iron and are then transported back into the bacterial cells.

Although most bacteria use only one siderophore, researchers at the University of Michigan confirmed what was suggested by the Bacillus anthracis genome: Anthrax actually contains genes for two distinct siderophores. This was a surprising result since siderophores are energetically costly for a bacterium to manufacture. Why would anthrax need a second mystery siderophore in addition to the well-studied “bacillibactin”?

This finding became even more intriguing when it was discovered that only the mystery siderophore was necessary for bacterial infection in mice; bacillibactin’s presence was altogether irrelevant. UC Berkeley chemistry graduate students Rebecca Abergel and Trisha Hoette, members of Kenneth Raymond’s laboratory, were contacted by B. Rowe Byers of the University of Mississippi Medical Center and asked to determine the identity of the mystery siderophore. Working with culture filtrates, which contain anthrax chemicals without being infectious, they discovered that the second siderophore, known as petrobactin, had never before been seen in a pathogenic species. Furthermore, while bacillibactin’s protein structure resembles that of other commonly observed siderophores, the structure of petrobactin is unique.

The final piece of the puzzle came from Roland Strong, a researcher at the Fred Hutchinson Cancer Research Center in Seattle, who had studied dual-siderophore systems before. Strong discovered that mammals have a natural immune protein, known as siderocalin, that binds and deactivates siderophores in E. coli and Salmonella enterica.

In a Proceedings of the National Academy of Sciences paper, Abergel and Hoette showed that this same siderocalin intercepts bacillibactin, but cannot bind petrobactin’s unusual structure. As a result, anthrax is able to use petrobactin as a stealthy iron-scavenging molecule that can do its job while evading the body’s natural immune defenses. Without this scavenger, anthrax’s explosive growth may not be possible. Bacillibactin may just be an evolutionary memento from the times before siderocalin inhibition kicked in. Since different species of bacteria often use similar mechanisms, Raymond and his students hypothesize that knowledge of siderophore use in anthrax can be applied to build drug therapies against other pathogenic bacteria in the future; the goal has always been to go further than just one pathogen.

Abergel emphasizes that the group’s achievements in the basic research of iron-harvesting mechanisms were really the root of this anthrax-specific breakthrough. “Our group has been studying iron uptake for 30 years, but this is the first time we’re figuring out how the immune system interacts with this mechanism. By discussing anthrax, we’ve gotten more press than ever before, but I think that these strategies of understanding bacterial growth may give us a more general way to build antibiotics.” Adds Hoette, “Iron can be a universal roadblock for all bacteria. If the immune system thinks it’s a good idea, we do too.”

Natasha Keith is a graduate student in chemistry.

Want to know more? Check out:
Abergel RJ. et al, (2006). Proc. Natl. Acad. Sci. 103(49):18499-18503.

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