Development of metallo-beta-lactamase inhibitors
The long term goal of this project is to create novel compounds with broad-spectrum inhibitory potency to MβLs and superbugs, and to provide a deeper understanding of molecular processes behind antibiotic action that is expected to support the development of additional antibacterial drugs.
The project is funded by the Swedish Research Council (Framework grant 2013-8804) and CARe.
Participants: Mate Erdelyi, Dep. of Chemistry and Molecular Biology at GU and Ke-Wu Yang at Northwest University in China.
The appearance of superbugs producing metallo-beta-lactamases (MβLs) have resulted in a clinical crisis. In this project, subclasses of MβLs including NDM-1 are expressed and purified and a a series of beta-lactam antibiotics transition state analogs are synthesized. Their broad-spectrum inhibition activity and structure-activity relationship is evaluated. Special attention is given to possible synergestic effects when applied in combination with antibiotics for inhibition of antibiotic resistant bacteria. The complexes of MβLs and the transition state analogs are studied by solution NMR and X-ray crystallography, to provide information useful for the development of clinically applicable broad spectrum inhibitors. The long term goal of this project is to create novel compounds with broad-spectrum inhibitory potency to MβLs and superbugs, and to provide a deeper understanding of molecular processes behind antibiotic action that is expected to support the development of additional antibacterial drugs.