Bacillus anthracis alias anthrax is a proven agent of biological terrorism. Pulmonary anthrax, in which spores of the anthrax bacteria are inhaled, is typically fatal unless diagnosis is made at an early stage of infection, when antibiotics such as Ciprofloxacin can provide a complete cure.
At late stages in the disease, antibiotics can kill the anthrax bacteria, but do not affect LF secreted by the bacteria, which is sufficiently concentrated in the bloodstream. LF enters cells and inactivates a human protein called mitogen-activated protein kinase disrupting the normal signalling pathways of the cell and inducing cell-death.
Using a fragment-based approach based on assays conducted with highly sensitive NMR techniques developed in a Burnham Institute's laboratory by a team led by Maurizio Pellecchia, Ph.D., the scientists were able to identify a scaffold that served as a template for designing a preferred structure for small-molecule inhibitors of LF. Lead compounds were synthesised and validated as highly potent and selective against LF in vitro. In in vitro assays, the compounds did not affect prototype human metalloproteinase enzymes that are structurally similar to LF. This is very important as selectivity is a fundamental prerequisite for a drug to be safe for use in humans.
Three lead compounds where tested in mice infected with anthrax spores, in combination with the antibiotic Ciprofloxacin. The survival rate for mice treated with each of the compounds tested in the combination therapy was two-fold over mice treated with Ciprofloxacin alone.
”This represents a significant advance in developing a possible emergency treatment for anthrax,” said Pellecchia. "We are working on refining the chemical structure of the compound with the goal of achieving an even more potent and selective drug that should exhibit a higher degree of protection against anthrax.”
MEDICA.de; Source: Burnham Institute