Scientists have identified a new target for an old drug that has been used to treat tuberculosis for over 50 years. This finding, reported in the May 2006 issue of Nature Structural & Molecular Biology, should be useful for designing new antitubercular compounds.
Tuberculosis is a global health threat, and an estimated two million people die each year of the disease. The drug isoniazid is the first line of defense against the bacteria that cause the disease. It is processed by an enzyme in the microbe, and one of the resulting products interferes with the synthesis of the bacterial cell wall, thereby quickly killing the pathogen.
Blanchard and colleagues now find that isoniazid targets another process essential for the survival of the tubercular bacteria. They show that a different product from isoniazid processing inhibits an enzyme called DHFR, which is important for the synthesis of nucleic acid building blocks. The authors further demonstrate in detail how DHFR is inhibited by the isoniazid metabolite. These results may explain the emergence of some drug-resistant tubercular bacteria observed in the clinic and should provide a foundation for engineering new drugs for treating the disease.
John Blanchard (Albert Einstein College of Medicine, Bronx, NY, USA)
Abstract available online.
(C) Nature Structural & Molecular Biology press release.
Message posted by: Trevor M. D'Souza