bacPROTAC2: targeting endogenous substrates for degradation

Bacteria play an important role in many environmental processes and inside the human body. However, there are also bacteria that can cause diseases ranging from mild to very severe. Antibiotics are used to fight disease-causing bacteria, but unfortunately, more and more of them become resistant to existing antibiotics. As a result, some dangerous diseases can no longer be treated. For many years, antibiotics research has stagnated: new ones that become available are often just variations of existing ones - and soon fail to work on antibiotic-resistant bacteria. To overcome this, we will need new antibiotics with completely different ways of killing bacteria. This project seeks to develop such a novel class of antibiotics. In our preceding project, we developed the first step of a potential new mechanism of action, called bacPROTAC. Instead of inhibiting a bacterial protein, bacPROTACs use a specific molecule to deliver a protein to the cell`s own quality control center. There, a cellular shredder breaks down proteins that are no longer needed into their individual building blocks and recycles them. In the case of the bacPROTAC antibiotic molecule, an essential protein is delivered to the shredder. Essential proteins are vital for bacterial cells and if their function is disrupted or they are even destroyed, the bacterial cell also dies. In this project, I plan to further develop the bacPROTAC concept. Essential proteins will not be delivered directly to the shredding machine, but to an enzyme called McsB. McsB normally marks non-functional proteins for destruction. I aim to repurpose McsB to mark essential proteins for destruction and thus kill the bacterial cell. I want to find out if 1) the enzyme McsB, which tags proteins for destruction with a molecular label, can be used for bacPROTACs; and 2) if there are essential proteins that can be targeted for bacPROTAC development. Both parts of the project should provide clues on how to develop novel antibiotics to fight multidrug resistant strains of dangerous bacteria.