Rhamnose biosynthesis: alternative antibacterial targets

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. In this research project we will focus upon the discovery, using a combination of chemical and enzymatic synthesis, of new potential drug leads for bacterial infections that work by specifically targeting a biosynthetic pathway found in bacteria and not in mammalian cells. This pathway is found in all gram positive, gram negative and mycobacteria making it an attractive target for the development of a broad-spectrum antiinfective. 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. Crystal structures of the specific enzyme we are planning to inhibit are known, making it possible for us to use structural insight in the design of our inhibitors. We have already demonstrated our expertise in the evaluation of the enzymes from three different bacterial pathogens in in vitro studies, and we have demonstrated our expertise in the chemical synthesis of potential enzyme inhibitors. We will make molecules that are structurally different to many known antibiotics, thereby exploring new chemical space. Our approach to making the drug leads will involve both chemical synthesis and enzymatic synthesis. We will use enzymes for specific transformations where it is not possible, due to stereoelectronic and mechanistic reasons, to use chemical synthesis. Compounds will be evaluated as (i) specific enzyme inhibitors (IC50 and Ki); (ii) against bacterial cells (MICs); and (iii) for toxicity using healthy human kidney and liver cells.