Rhamnose biosynthesis: alternative antibacterial targets

Projections indicate that by 2050 drug resistant bacteria will kill more people than will cancer. Methicillin-resistant Staphylococcus aureus (MRSA) is one of many emerging new bacterial infections arising from drug resistance. The viability of Caesarean sections, chemotherapy and transplant surgery depends on antibiotics being able to treat infections. Bacterial resistance is increasing at a dramatic rate. 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 discovery arena. The goal of this research project is to rationally design novel chemical entities (NCEs) for bacterial infections combining chemical and enzymatic approaches. These NCEs are designed to target a specific biosynthetic pathway found in Gram-positive bacteria, Gram-negative bacteria and mycobacteria thereby making it an attractive target for the development of a broad-spectrum anti-infective. This pathway is not 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, nor is the pathway present in mammalian cells. Our inhibitors are designed using knowledge of enzyme mechanism and structure. We have synthesized NCEs that bind multiple enzymes in the pathway. We have developed NMR methods to demonstrate binding and coupled spectrophotometric kinetic assays for enzymological analysis. Our NCEs will enhance our preliminary activities by a factor of 10-1000. With these improved NCEs to hand, we will initiate prodrug development to improve cellular activity and toxicity testing in cells as a prelude to preclinical evaluation. Local and national collaborators have been identified to facilitate development of the most promising candidate molecules synthesized.