Structural Basis of Macrolide Sensitivity and its Impacts on Antibiotic Design and Use

Summer 2016

Daniel Srole : MCB: Biochemistry & Molecular Biology

Mentor: Jamie Cate

With our overuse of antibiotics and the resulting decline in their effectiveness, it has become increasingly important to understand their mechanisms of action.  Many antibiotics act on harmful bacteria by targeting ribosomal processes and disrupting the translation from mRNA to proteins, thereby interrupting gene expression.  The cell’s abilities to function and reproduce are thereby disrupted, and we observe the desired effects of antibiotics rather quickly.  Macrolides are a class of antibiotic that works in this way.  The binding site for these molecules in prokaryotes is highly conserved in eukaryotes.  With such a large similarity, it is not known exactly why eukaryotes are resistant to their effects.  No prior research has found the structural basis that confers macrolide sensitivity to prokaryotes but not to eukaryotes.  By probing the macrolide binding pocket in both, I hope to discover mutations that remove macrolide sensitivity in prokaryotes as well as those that confer it in eukaryotes.  If successful, we will be able to piece together an understanding of macrolide function.

I almost can’t put into words how thankful I am for the opportunity to be a SURF fellow. It allows me to not only be surrounded by the greatest minds in biochemistry and molecular biology, it allows me to interact with them on a regular basis, and lead my own project to join them in expanding our collective scientific knowledge. My PI Jamie Cate, my mentor Dr. Elizabeth Montabana, and the entire Cate lab have been great role models and teachers to me. They have all done so much for me, and I can’t thank them enough. Someone once described research to me as what happens when you reach the end of a textbook and still have questions. Thanks to the SURF program and the Rose Hills Foundation and sponsors, I'm able to put down the textbook.