Novel Ways of Combating Tuberculosis: Hopes for a Better Treatment

Anusha Raja | anusha.raja@yale.edu October 1, 2010

A Yale research team led by Thomas Steitz, Nobel Laureate and Sterling Professor of Molecular Biophysics and Biochemistry, has discovered how a family of tuberculosis-fighting antibiotics combats tuberculosis (TB). This discovery may pave the way for new antibiotics that can overcome the problem of drug resistance.

According to the World Health Organization, contagious air-borne strains of Mycobacterium tuberculosis have infected more than two billion people and caused over nine million new TB cases each year. This disease of poverty affects mostly young adults, debilitating many developing nations’ work forces. Currently, when treated with antibiotics, patients can recover with an 87% global success rate. Many public health officials are, however, concerned about the emergence of multi-drug resistant TB and extensively-drug resistant TB, both of which are bacilli that cannot be treated with current antibiotics.

Today, over half of TB antibiotics function by interfering with the bacteria’s protein-producing organelles, the ribosomes. According to Steitz, the lab had been looking “at a very large number of antibiotics that bind to the large subunit.” Gregor Blaha, one of the lab’s primary researchers, suggested focusing on the structure and mechanism of these large ribosomes, which play crucial roles in their interactions with antibiotics.

By examining the structure of the interaction complex, the Steitz lab was able to explain why the antibiotics affected translation in TB bacteria. The researchers focused on how viomycin and capreomycin, members of the tuberactomycin family of antibiotics, interacted with the 70S ribosome. Using X-ray crystallography, the lab discovered that the two antibiotics were both binding to the ribosomal decoding center—the mRNA binding site where tRNA recognizes the genetic code during translation. According to Steitz, in the highly-conserved intersubunit bridge between helix 44 of the small ribosomal subunit and helix 69 of the large ribosomal subunit, “the anticodon of the tRNA interacts with the codon of the message; the ribosome [holds] all these pieces together.” When an antibiotic like capreomycin binds to this binding site, it traps the ribosome when tRNA recognizes the codon, ultimately preventing translation of the mRNA. Crucial protein synthesis consequently cannot occur, thereby killing the bacteria.

The lab also found that paromomycin and hygromycin B, two other families of TB antibiotics, interact with both the ribosomal sites adjacent to this junction and with capreomycin, affirming the significance of this site to protein synthesis. “Once you’ve solved the structure of the ribosome without the antibiotic, the process of looking at complexes with various types of smaller molecules bound to it was pretty straightforward,” says Steitz.

These findings have provided Steitz with a new way of approaching the manipulation of antibiotics. Steitz explains that this discovery is a “starting point idea for how one can modify capreomycin to add additional groups.” With this new information regarding the structure, Steitz hopes that his company, Rib-X Pharmaceuticals Inc., will be able to develop new antibiotics to treat infections like methicillin-resistant Staphylococcus aureus (MRSA).

Sources:

[1] http://www.who.int/tb/publications/factsheets/en/index.html – for statistics

[2] Stanley, Robin E., Gregor Blaha, and Thomas A. Steitz. “The Structures of the Anti-tuberculosis Antibiotics Viomycin and Capreomycin Bound to the 70S Ribosome.” Nature Structural & Molecular Biology 17 (2010): 289-93. Nature Structural & Molecular Biology. Nature, 14 Feb. 2010. Web. 26 Mar. 2010. http://www.nature.com/nsmb/journal/v17/n3/full/nsmb.1755.html.

[3] Interview with Professor Thomas Steitz, Nobel Laureate, Sterling Professor of Molecular Biophysics and Biochemistry, Interviewed 3/25/10, Fact Checked 3/31/10

[4] Yale University Office of Public Affairs. Yale Researchers Find New Way to Attack a Dangerous TB Strain. Yale Bullentin. Yale University, 14 Feb. 2010. Web. 26 Mar. 2010. http://opa.yale.edu/news/article.aspx?id=7285.