Vol 5. Issue 7 / February 28, 2005
Attacking Anthrax on Two Fronts
By Jason Socrates Bardi
Much tragedy ensued in the months following the contamination of newsrooms, post offices, and U.S. Senate offices a few years ago with deadly Bacillus anthracis spores. Several people died terribly of inhalation anthrax, post offices and other places of business on the East coast were closed for decontamination, and panic in a Chicago nightclub killed 21 people who were trampled by clubbers fleeing what they thought was a chemical attack.
Along with these tragic events came a bizarre and widespread hysteria—causing many false alarms over substances such as baby powder and leading one man in upstate New York to enshroud his home in plastic and tape like a scaled-down, rural Christo and Jean-Claude exhibit.
Perhaps one reason for the hysteria was a growing public awareness that the front line treatment medical science could offer to fight anthrax was Cipro®. Not that Cipro® is without efficacy—it is a potent antibiotic that readily kills the bacteria, and it is approved by the U.S. Food and Drug Administration for treating people exposed to B. anthracis. But because B. anthracis produces a virulent toxin that kills cells and, in high enough doses, infected people, the effectiveness of Cipro® diminishes if exposure is not detected quickly enough. That's the rub—even if the infection is brought under control, the bacteria may have produced enough toxin to be lethal.
“The release of toxin is the major problem [in anthrax infections],” says Professor Chi-Huey Wong of The Scripps Research Institute in La Jolla, California. “It’s an enzyme, so even a small amount released in the body can be deadly.”
Finding a way to neutralize the effect of the toxins would be a great boon to public health preparedness against anthrax exposure.
Now a team of scientists led by Wong at Scripps Research and by Professor Timor Baasov of the Institute of Catalysis Science and Technology Technion–Israel Institute of Technology in Haifa, Israel, is reporting that it has found a potential way of improving treatment: it has discovered a class of antibiotic derivatives that targets not only the bacteria, but also the anthrax toxin.
The anthrax "toxin" is actually a system of molecules composed of three separate proteins released by the bacterium. Two are virulent proteins that interact with human cells. This is the "lethal factor," which is a metalloprotease (an enzyme that chops up other proteins), and the "edema factor," which is an adenylate cyclase (a protein that makes cAMP, an important "second messenger" molecule in the body that has a variety of systemic effects).
The third protein produced by the bacterium, called protective antigen, is important for getting lethal factor and edema factor into cells. Protective antigen binds to the surface of human cells and forms a sort of cat’s door that allows the lethal factor and edema factor to pass through to the interior of the cell where they do their damage. Once inside cells, the lethal and edema factors lead to cell death.
The details of how the lethal and edema factors kill cells are still somewhat murky, but what is clear is that protective antigen, lethal factor, and edema factor work together to make Bacillus anthracis deadly. Of the three, lethal factor makes a tantalizing target for drug design because strains of anthrax unable to produce lethal factor are not pathogenic, which means that blocking this protein may be enough to save lives.
Wong and his colleagues set out to design antitoxins that could be used to target lethal factor by using in vitro and cell-based assays to screen a library of about 3,000 chemical compounds for those that have the ability to bind to and inhibit anthrax’s lethal factor.
Among the compounds in this library were a number of aminoglycosides, including neomycin B, a common antibiotic and the main component of Neosporin®. Structurally, neomycin is markedly different from most known protease inhibitors. “Nobody would have guessed that it could inhibit anthrax’s lethal factor,” says Wong, who holds the Ernest W. Hahn Professor and Chair in Chemistry and is a member of The Skaggs Institute for Chemical Biology at Scripps Research.
But screening showed otherwise. Neomycin B bound to lethal factor in the test tube and inhibited the lethal factor-induced signaling pathway in cell-based assays.
Wong and his colleagues then made derivatives of neomycin though chemical synthesis. When they tested these, several of them looked even more effective at binding to and inhibiting lethal factor.
Significantly, because the neomycin derivatives are all aminoglycosides, they also have the ability to bind to the ribosomal RNA of the anthrax bacterium itself, thus inhibiting its normal functioning. The team is now performing experiments to test how effectively its compounds protect human cells.
The article, “Dual Effect of Synthetic Aminoglycosides: Antibacterial Activity against Bacillus anthracis and Inhibition of Anthrax Lethal Factor” by Micha Fridman, Valery Belakhov, Lac V. Lee, Fu-Sen Liang, Chi-Huey Wong, and Timor Baasov was published in the journal Angewandte Chemie 44(3) pp. 447-452 (2005). See: http://dx.doi.org/10.1002/anie.200462003
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