Antibiotics, toxins, and protein engineering

Lectures: 1 session / week, 2 hours / session

A basic knowledge of the central dogma of molecular biology: DNA → RNA → protein.

The lethal poison Ricin - best known as a weapon of bioterrorism, Diphtheria toxin - the causative agent of a highly contagious bacterial disease, and the widely used antibiotic tetracycline have one thing in common: They specifically target the cell's translational apparatus and disrupt protein synthesis.

In this course, we will explore the mechanisms of action of toxins and antibiotics, their roles in everyday medicine, and the emergence and spread of drug resistance. We will also discuss the identification of new drug targets, and how we can manipulate the protein synthesis machinery to provide powerful tools for protein engineering and potential new medical treatments for patients with devastating diseases such as cystic fibrosis and muscular dystrophy.

Protein synthesis is a fundamental and ancient process that has been highly conserved in all cells from bacteria to human. Protein synthesis takes place on the ribosome and requires many protein and RNA factors to ensure timely and accurate translation of the mRNA. Because of the essential and ubiquitous role of proteins in all cells, protein synthesis has been a prime target of antibiotics and toxins that can effectively shut down translation and cell function. Bacteria, fungi and plants produce various compounds that are extremely potent inhibitors of translation and therefore toxic to cells. The overall mechanism of protein synthesis is similar in all kingdoms of life. However, there are some essential structural differences between the protein synthesis machineries of bacteria and eukaryotes that allow for highly selective inhibition of protein translation in one kingdom but not another. This selective inhibition has important medical implication, as it is the basis of antibiotic usage to combat bacterial infections.

In this course, we will cover protein translation in detail and discuss the scientific literature that investigates the mechanism of action of protein synthesis inhibitors such as Ricin, Diphtheria toxin, and some major antibiotics (e.g. tetracycline). We will also learn about diseases caused by various defects in the translational machinery and possible new medical treatments. Finally, we will discuss cutting-edge methods that are currently being developed to "twist and tweak" normal protein synthesis for the purpose of protein engineering.

The main objective of this course is to familiarize students with the primary scientific literature (in print and on-line databases) while you discover the exciting world of protein synthesis. You will learn how to read, analyze and critically evaluate scientific papers, and you will be encouraged to engage in active class discussions. The course will provide fundamental insight into the structure and function of the ribosome, its role in protein synthesis, structure and function of the ribosome, and mechanism of action of antibiotics and toxins that target translational machinery. A strong focus will be on the methodology and experimental approaches used, from basic biochemistry, genetics, and molecular biology, to state-of-the-art protein engineering.

Most meetings will consist of discussion of two research papers. Students are expected to have read the papers in advance, use on-line literature databases for optional background reading, and be prepared to discuss the selected papers in class. At the end of each class, the necessary background to understand the papers for the next session will be provided.

There are two projects on the following topics:

Project 1: Screening for new drug targets.

Project 2: Site-specific incorporation of L-acetyl-phenylalanine and L-benzoyl-phenylalanine into a target protein (X) in mammalian cells.

Successful conclusion of the course requires the completion of two projects. Attendance at all meetings is very important, and no more than one class can be missed. Students who miss a class must complete a make-up assignment, which will consist of a 1-2 page (double-spaced) summary of the papers discussed in that particular meeting.

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