Grant: Discovery Grants Program - Individual

Antibiotic resistance to bacterial infections is a major concern to health care systems. Hence new and alternative strategies to fight diseases are required and amongst these, prophylactic methods such as vaccinations have been extremely successful. Important infectious diseases like pneumonia, tuberculosis, and meningitis have been eradicated in developed countries due to massive vaccination programs. In this regard, our group has previously contributed to the commercialization of two such vaccines. We are proposing herein two novel and promising approaches aimed at preventing the early stage of infections by a) blocking bacteria from attaching and colonizing host tissues by virtue of their carbohydrate binding proteins present at the tip of their pilli and b) by stopping the assembly of these pilli using new therapies called pilicides. The likelihood of developing resistance is therefore greatly reduced since bacteria cannot mutate their carbohydrate receptors without impeding their attachment processes. Cell surface carbohydrates present on human epithelial linings as glycolipids and glycoproteins are responsible for the bacterial recognition and attachment. These binding interactions are usually weak but nature has circumvented this problem by using multiple copies of the binding partners. Our proposal is based on the design of new nanometric molecules (glycodendrimers) that also expose several copies of the carbohydrates in order to foul the bacteria by binding and surrounding them with high affinity, thus preventing their attachment. In order to simplify the preparation associated with complex carbohydrate structures, we use fundamental aspects associated with medicinal chemistry. With this strategy in mind, simpler carbohydrate ligands will be prepared using modern synthetic methods. The rapid and efficient assembly of highly branched glycodendrimers using popular chemical processes (""click chemistry""), heterocyclic pharmacophores, and pro-drug construction will be undertaken. The diseases targeted with this approach are urinary tract infections caused by E. coli, Pseudomonas aeruginosa involved in cystic fibrosis, and cancer cell metastasis.