Mechanism of action of Carbapenemases, and development of inhibitors against these
In this project we investigate by means of high-level QM/MM-methodology, the mechanism of action of carbapenemases, and in particular KPC-2, towards representative compounds from the different classes of beta-lactam antibiotics to better understand detailed structural and electronic features.
The project is funded by the Swedish Research Council (Framework grant 2014-3914) and CARe.
Participants: Prof Leif A. Eriksson (PI), Prof Johan Gottfries and Sonali Chavan (PhD student), Dep. of Chemistry and Molecular Biology at GU.
The occurrence and spread of beta-lactamases capable of hydrolyzing carbapenems, and thus essentially all existing beta-lactam based antibiotics, is a major health threat. In this project we investigate by means of high-level QM/MM-methodology, the mechanism of action of carbapenemases, and in particular KPC-2, towards representative compounds from the different classes of beta-lactam antibiotics to better understand detailed structural and electronic features. With this information we aim to provide detailed knowledge to enable development of both broad-hitting and highly carbapenemase-specific inhibitors. The work is done on parallell with extensive vitrual high-throughput screening to identify new compounds with antibiotic activity, and inverse docking techniques to compare binding specificity towards different classes of compounds and between different carbapenemases, and potential adverse side effects.