Rhamnose biosynthesis: alternative antibiotic targets

Bacterial resistance is increasing, so there is a pressing need to discover new medicines to treat infectious diseases. We will perform drug innovation and prepare molecules with new antibacterial activity. These molecules are new and have not been prepared previously. Methicillin-resistant Staphylococcus aureus (MRSA) was responsible for more deaths in North America in 2007 than HIV / AIDS and is one of many emerging new bacterial infections arising from drug resistance. There is a limited choice of drugs available to manage infections from drug resistant bacteria. This indicates that there is a strong need to develop new antibacterial drugs, yet pharmaceutical companies are exiting the infectious diseases area. In this research project, we will use chemical and enzymatic methods to discover new potential drug leads for bacterial infections. These new molecules are designed to specifically target a biosynthetic pathway that is found in bacteria but not in mammalian cells. This pathway is found in all gram positive, gram negative and mycobacteria thereby making it an attractive target for the development of a broad-spectrum anti-infective. This pathway has not previously been targeted by any currently approved drugs, nor by any known natural products, nor is there any significant work in the literature regarding the inhibition of this pathway. Our inhibitors are designed using knowledge of the enzyme(s) mechanism and structure. We have already demonstrated our expertise in the evaluation of the enzymes from different bacterial pathogens in in vitro studies, and we have demonstrated our expertise in the chemical synthesis of potential enzyme inhibitors. We have developed NMR methods to evaluate binding. We will make molecules that are structurally different to many known antibiotics, thereby exploring new chemical space. Compounds will be evaluated as specific enzyme inhibitors (IC50 and Ki), against bacterial cells (MICs), and for toxicity using human kidney cells.