“Soil Science”: Streptomycin and the Treatment of Tuberculosis (TB) Gabriela Farfan, Samuel Huang, Susan Huang, Joy Li, JunYao Song, Peter Vander Velden, Connie Wang, Mary Zhang Madison West High School, Madison, WI 53726 Advisor: Basudeb Bhattacharyya, University of Wisconsin, Madison, WI 53706 Mentor: Dr. Dave Nelson, University of Wisconsin, Madison, WI 53706

Introduction Bacterial Protein Translation What is Tuberculosis? Tuberculosis (TB) is an infectious disease caused by Tuberculosis is a disease caused by the the bacterium Mycobacterium tuberculosis . It bacterium Mycobacterium tuberculosis commonly attacks the lungs, but it can also affect other parts of the body such as the nervous system or the that spreads through air and attacks the circulatory system. Approximately one-third of the the lungs. Prior to 1943, tuberculosis left world population is infected with M. tuberculosis , but untreated had a high mortality rate in the they have a latent form of the disease that only has a United States. Streptomycin, an antibiotic, 10% chance of developing into active TB. The TB the first cure found for tuberculosis, was bacterium is spread through inhaling infected aerosol isolated from the soil organism droplets when infected persons cough or sneeze. Once Streptomyces griseus in 1943. it has entered the lungs, M. tuberculosis invades and replicates within alveolar macrophages. Lesions occur We are using rapid prototyping technology at the Ghon focus, typically between lobes in the to model the interaction between lung. From the lungs, the bacillus can spread to other parts of the body through the bloodstream although streptomycin and the 30S bacterial it rarely affects those other parts. When a person gets ribosomal subunit of RNA. This antibiotic an active TB infection, they do not feel well and cough binds tightly to bacterial 16S rRNA, up mucus or blood among other symptoms. Left causing protein translation to be “error– untreated, TB has a 50% mortality rate. prone”. As a result many defective Tuberculosis proteins are synthesized, and the cell dies. This process does not affect human affecting the lungs ribosomes because human ribosomes do not have the 16S rRNA. By modeling the mechanisms of this antibiotic, we hope to further understand the general mechanisms of bacterial infection and antibiotic treatment as well as antibiotic resistance.

Nelson, D. and Cox, M. (2003) This process continues until Lehninger Principles of Biochemistry, Freeman Publishers, These pictures show TB lesions in the lung. As shown a complete protein is New York synthesized. in (1), these lesions typically occur between lobes at the Ghon focus. TB is shown in an advanced stage in

Streptomycin: Structure (2). http://gallery.unl.edu/images/75-sw/75-sw-88.gif http://www.med.yale.edu/intmed/cardio/imaging/cases/tuberculosis_hilar_ad/graphics/rad1. and Function tRNA-AAs bind to anticodons in the gif Streptomycin affects peptide (P) and acceptor (A) sites.

the A site Peptides are transferred from the tRNA Conclusions in the P-site to the tRNA-AA in the A- •Streptomycin kills bacteria by compromising the site. ribosome. •Streptomycin is an effective antibiotic because its structure is similar to that of the anticodons that would A new tRNA-AA enters the A site and usually bind to the ribosome. www.bioscience.utah.edu www.alanwood.net the old original tRNA exits the E-site Streptomycin affects the ribosome by binding •Streptomycin is significant because it was the first the A site where tRNA usually binds. Shown Streptomycin changes the conformation antibiotic that could treat tuberculosis. above, is an anticodon, tRNA (1), and of the A-site of the ribosome. This •Over time, bacteria have become resistant to streptomycin (2). Notice the structural causes the ribosome to be “error-prone,” streptomycin. similarities between streptomycin and the leading to the synthesis of defective anticodon that allow streptomycin to fit into the proteins. This leads to cell death. •By studying the structure of streptomycin, new antibiotics can be developed to combat diseases such binding site for anticodons and disrupt http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/imag es/agmiscode01_illus.jpg as TB. Supportedtranslation. by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA)