The UC Berkeley scientists, working with colleagues at the University of Mississippi Medical Center in Jackson and the Fred Hutchinson Cancer Research Center in Seattle, uncovered the trick while studying how these deadly bacteria steal iron from their human hosts to grow and reproduce.
"Humans make a protein called siderocalin to defend against bacteria in the continual arms race between pathogen and host. This is the first example of a protein produced by the human immune system that disrupts bacteria's iron scavenging system," said Ken Raymond, UC Berkeley professor of chemistry and faculty scientist at Lawrence Berkeley National Laboratory.
Anthrax bacteria are known to produce two small molecules - bacillibactin and petrobactin - that snatch iron away from the human body's iron transporter molecules, called transferrin. These scavengers, or "siderophores," are essential to anthrax's ability to grow rapidly, especially after the spores are inhaled, though why the bacteria need two siderophores to do the job has been an enigma.
The new study shows why anthrax bacteria require two siderophores working by two different mechanisms. Siderocalin, the human immune protein, binds bacillibactin and effectively sidelines it, the researchers found. Apparently, anthrax fielded a second "stealth" iron scavenger, petrobactin, to get around the human defense against the first scavenger. Petrobactin is not bound by siderocalin.
As far as is known, the human immune system has yet to launch a successful counterattack against the stealth siderophore, but that doesn't mean humans can't design one of their own, according to Raymond. His UC Berkeley team and the Seattle team are now exploring how their discovery could be used to diagnose or treat anthrax.
The researchers published their findings Nov. 28 in the online edition of the Proceedings of the National Academy of Sciences. Their paper will appear in the Dec. 5 print edition.
Many bacteria, including the benign Escherichia coli in our gut, make small molecules called siderophores that snatch iron from the tissues of their host so that the bacteria can reproduce. Some strains of E. coli produce more than one kind of siderophore, apparently attacking on several fronts to get the iron they need.
The discovery of a similar strategy in anthrax, Bacillus anthracis, suggests that producing more than one siderophore is a general strategy of bad as well as benign bacteria, according to the researchers. To date, however, only the pathogenic forms of E. coli and Bacillus have been found to produce a siderophore not bound by siderocalin; the non-pathogenic forms that produce more than one siderophore base them on the same molecular structure to which siderocalin binds.
Anthrax is a potential bioweapon because it is nearly always fatal when inhaled. Its long-lived spores grow rapidly in the lungs, leading to breathing problems and shock within days. While a vaccine is available, there is no effective treatment.
The bacteria succeed by forming capsules that invade lung cells, then capturing iron in order to reproduce, and finally, manufacturing a toxin that kills the cells and releases thousands of new spores into the bloodstream.
Because the iron-capture stage is critical to growth, it has become a recent focus of attention as a possible drug target. Raymond, who has studied bacterial siderophores that capture iron for 35 years, recently teamed up with Roland Strong of the Seattle cancer center to study siderocalin, a human protein Strong had found that appeared to interfere with the siderophores secreted by anthrax bacteria.
To study the role of this protein, Raymond and UC Berkeley graduate students Rebecca J. Abergel and Trisha M. Hoette approached an anthrax research laboratory run by B. Rowe Byers, professor of microbiology at the University of Mississippi Medical Center, to obtain samples of anthrax siderophores. Because bacteria secrete siderophores, these molecules can be separated from the bacteria and studied without danger of infection.
Using these anthrax bacteria extracts, Abergel and Hoette isolated the two siderophores, bacillibactin and petrobactin, and showed that siderocalin tightly binds bacillibactin, preventing it from capturing iron from human cells. However, siderocalin does not prevent petrobactin from binding iron.
Interestingly, bacillibactin is very similar to siderophores in other bacteria, including enterobactin, which is produced by several pathogenic bacteria that live in the gut, such as Salmonella enterica and pathogenic strains of E. coli. These two bacteria also contain a second siderophore, aerobactin, with a molecular structure similar to petrobactin.
The researchers suggest that producing a second, stealth siderophore - petrobactin or aerobactin - that has a different molecular structure than bacillibactin and enterobactin may be a common response by bacteria to the human body's production of siderocalin.
The research could lead to anti-anthrax drugs that target petrobactin synthesis or iron-uptake, or to anthrax sensors that detect petrobactin, which is not known to occur in any other pathogenic bacteria.
Robert Sanders | EurekAlert!
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy