Concepción González-Bello
Universidade de Santiago de Compostela
Spain
Title: Targeting the Motion of Shikimate Kinase – Opportunities for Antibiotic Drug Development
Biography
Biography: Concepción González-Bello
Abstract
The increasing development and spread of resistance to current antibiotics have turned ordinary bacterial infections into illnesses that cannot be controlled. Infections from resistant bacteria are now too common and some pathogens have even become resistant to multiple types of antibiotics. Therefore, it is urgent to search for new antibacterial agents and approaches to face the challenge of multidrug resistance. The disruption of the growth cycle by preventing the synthesis and assembly of key components of bacterial processes is the most widely used strategy to combat bacterial infections. Most current antibiotics that are highly successful in human clinical use, surprisingly targeted at only four main key processes and resistance to these antibiotics is widespread and well known. Therefore, the search for unexplored bacterial functions appears to be a good option for the development of novel antimicrobial agents with a new mechanism of action. For this purpose, our research group is studying the possible development of new antibiotics whose mode of action is based on the selective and effective inhibition of an essential enzyme in bacteria that does not have any counterpart in human cells, shikimate kinase (SK). This enzyme is essential in relevant pathogenic bacteria such as Mycobacterium tuberculosis, Helicobacter pylori and Pseudomonas aeruginosa. The starting point for our inhibitors design was the study of: (a) the substrate binding requirements, (b) the phosphoryl-transfer mechanism and (c) the essential enzyme motions for product release. Here we report results from NMR, biochemical, structural and Molecular Dynamics simulation studies that help understand the catalytic mechanism, the binding requirements and the essential enzyme motions for product release of the SK enzyme. Based on these results, potent reversible competitive inhibitors of the enzyme were developed. An ester prodrug approach was used for achieving good in vitro activities against H. pylori. Our recent results on this project will be presented