Angewandte Chemie International Edition
© WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44 (41), 447—452
Chemical Club with a One-Two Punch
Tailored antibiotics attack anthrax pathogen
The anthrax agent, Bacillus anthracis, can occur in animals anywhere on Earth. Humans can also be infected, so the biological weapons treaty of 1972 forbids use of the agent. It is, however, a possible terrorist weapon. The bacterium forms spores that can survive long exposure to unfavorable environmental conditions such as heat and dryness. They infect humans and animals through wounds in the skin, through the intestines if swallowed, or through the lungs if inhaled. Once inside the body, the anthrax spores wander into the nearest lymph nodes. There they germinate and form viable bacteria that multiply and produce the dangerous anthrax toxin. This then paralyzes the host’s immune system so that the bacteria can enter the bloodstream, where they rapidly multiply further, producing quantities of toxin deadly to the host.
Anthrax toxin consists of three components, of which a protein, known as the lethal factor, is most responsible for the fatal activity. This protein is thus a target for therapeutic approaches for treating the infection. Two groups of scientists, working with C.-H. Wong in La Jolla (CA, USA) and T. Baasov in Haifa (Israel), have now determined that the well-known aminoglycoside antibiotic Neomycin B locks onto the lethal factor under physiological conditions in vitro, inhibiting its activity. Starting from this basic structure, the scientists synthesized a new class of aminoglycosides that bind even more tightly to the toxic protein, deactivating it more effectively. In addition, these compounds battle the disease on a second front: they latch onto its genetic material, messing up the reading of the genes and thus hindering further multiplication of the bacteria.
The newly introduced Neomycin B derivatives highlight a very promising route to the synthesis of drugs that simultaneously hinder the growth of the bacteria and the effect of the anthrax toxin. Whether they also display this effect in living organisms and really do protect the cells of the immune system from attack by the toxin will now be tested in further experiments.