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. There is a limited choice of drugs available to manage infections from drug resistant bacteria. 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. These NCEs are designed to target a specific biosynthetic pathway found in Gram-positive, Gram-negative and mycobacteria, thereby making it an attractive target for the development of a broad-spectrum anti-infective. This pathway is not targeted currently, nor is the pathway present in mammalian cells, providing selectivity and limiting off-target effects. Our inhibitors are designed using knowledge of the enzyme mechanism and structure of the enzyme active site. The NCEs we have prepared are designed to covalently bind specific conserved active site residues. We have developed NMR methods to demonstrate binding and coupled spectrophotometric kinetic assays for enzymological analysis. With these NCEs, we will evaluate them against homologous gene products from Mycobacterium tuberculosis and the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp), a panel of highly virulent pathogenic bacteria able to evade commonly used antibiotics due to their increasing multi-drug resistance. Local, national and international collaborators have been identified to facilitate development of the most promising candidate molecules synthesized against the specific ESKAPE pathogens.