New challenges and opportunities in drug discovery targeting glutamate racemases: a structure-based perspective

Drug-resistant bacteria strains have become more and more prevalent, presenting the need for novel antimicrobial agents. In addition, drug candidates are slow to progress through clinical trials, requiring an immense amount of time and resources to gain FDA approval. This process has a high attrition rate, by which many drug candidates fail to show the efficacy and safety necessitated to advance to the market. The work presented here attempts to alleviate this high attrition rate through discovering novel molecules able to regulate a clinically relevant enzyme, glutamate racemase.

The enzyme glutamate racemase is responsible for the production of D-glutamate, which is then crosslinked to form the peptidoglycan layer of bacterial cell walls, without which bacterial cells are subject to lysis from osmotic pressure. Successfully targeting glutamate racemase presents an attractive pathway in combating drug-resistant bacterial infections. The first of these pathways is through covalent inhibition. This means that the inhibitor is bound to a catalytic amino acid residue in the active site preventing the enzyme from performing its intended purpose of producing D-glu. By targeting glutamate racemase in this way, infections caused by drug-resistant bacterial strains, such as pulmonary tuberculosis, may be treated with novel therapeutics.

The second pathway focuses on allosteric binding sites. Here compounds bind in a pocket other than the main catalytic site. Even though these binding sites are not the typical binding sites for compounds they still play a role in enzyme activity. Targeting these sites when developing drugs can avoid problems associated with targeting the active site, such as the poor ADME properties of compounds that bind in polar active sites and these pockets also afford the possibility of species specific inhibitors.