FREEZING THE ESSENTIAL MOTION OF KEY BACTERIAL ENZYMES – A STRATEGY FOR ANTIBIOTIC DRUG DISCOVERY

Concepción González-Bello

Dept. of Organic Chemistry, Universidade de Santiago de Compostela, CIQUS, Spain

Abstract

The decreased effectiveness of antibacterial agents against infectious diseases caused by the development of drug resistance has become one of the most important public health issues of the early 21st century. It is therefore urgent to develop new antibacterial agents and approaches to face the challenge of multidrug resistance. In recent years much research has been devoted to the identification of new and unexploited therapeutic targets involved in key processes for bacterial survival as well as a detailed knowledge of the basis of their behavior. Our research group is exploring the potential of the enzymes involved in the shikimic acid pathway for the development of novel antibiotics for the treatment of infections caused by H. pylori (stomach cancer) and M. tuberculosis (tuberculosis). Typical strategies for the design of inhibitors are based on docking or virtual screening studies using the available crystal structures in which the enzyme is considered as a rigid mold. As a consequence, the size and conformation of the potential ligands would be determined by the space available in the employed crystal structures. However, enzymes are ʿdynamicʾ systems that are able to adopt diverse conformations during catalysis and this could also be exploited in inhibitor design since the flexibility is essential for catalysis. By using this less exploited ʿmotion-based design approachʾ, reversible competitive inhibitors of two key enzymes of the shikimic acid pathway, type II dehydroquinase and shikimate kinase, were developed. These compounds reduce the flexibility of key enzyme domains, which motion is required for catalysis. An ester prodrug approach was used for achieving good in vitro activities against H. pylori. Our recent results on this project will be presented.

Keywords: Motion, enzyme inhibitors, shikimate kinase, dehydroquinase, M. tuberculosis, H. pylori.