Some human pathogen bacteria are hard to treat since they are resistant towards the currently used antibiotics. The beta-lactam family of antibiotics are the most widely used anti-bacterial agents to combat infections, and it includes penicillin and carbapenems among others. The most frequent resistant mechanism is the presence of enzymes (beta-lactamases) that cleave the antibiotic rendering the antibiotic inactive.
The focus in this project is to establish a highly interdisciplinary team of Indian and Norwegian experts, where we will develop novel inhibitors towards the enzymes the beta-lactamases. This inhibitor can be further be used together with the currently used beta-lactam drugs in a combination. This combination therapy will prolong the lifetime of our currently used beta-lactam drugs, and is one way of fighting the rapidly growing number of antibiotic resistance bacteria.
In India we have screen a big library and identified one inhibitor that is synthetized in bigger amounts in Norway. This inhibitor will now be tested in more cell based assays (India) and in biochemical assays (in Norway) to confirm the effect and determine the inhibitor potential towards other enzymes. Docking has identified a possible binding pocket.
We have bought a commercial library (1814 molecules) were India have identified 2 hits with cell based assays. The last commercially available inhibitors (Avibactam, Relebactam og Zidebactam) are now included in the inhibitor characterization for comparison and as positive controls. Our last results show one hit inhibitor against a metallo-beta-lactamase and improved inhibitors towards KPC.
This interdisciplinary project done in Norway and in India, where we have performed structure based inhibitor design, organic synthesis of improved Phenylboronic acid inhibitors that are found to be have better inhibitor efficacy to a serine beta lactamase enzyme. We have screening a big library and identified one inhibitor that is synthetized in bigger amounts in Norway. Unfortunately, this particular re-synthetized inhibitor did not show sufficient inhibitor effects in our experiments.
We have also identified a new promising inhibitor towards the hard to hit metallo-beta-lactamase NDM. The inhibitor has been investigated in a mice pneumonia model, to find the in vivo efficacy in combination meropenem. Here more work is needed to draw a final conclusion.
Why: Carbapenemase producing Gram-negative pathogens are associated with significant mortality and morbidity due to few options for diagnosis and treatment. The serine- based carbapenemases OXA-48 and KPC-2 are emerging in several clinical relevant pathogens.
What: We will focus on the development of inhibitors towards carbapenemases OXA-48 and KPC-2 harboring pathogens. By the establishment of a highly interdisciplinary team of Indian and Norwegian experts, we will develop novel inhibitors based on small molecules that can be used as adjuvants to re-potentiate carbapenem antibiotics. This combination therapy will prolong the lifetime of our currently used beta-lactam drugs.
How: This project will provide novel carbapenemase selective inhibitors by screening small molecule library towards pure OXA-48 and KPC-2; and synthesis of improved inhibitors. All binders will be subjected for their inhibitory potential in cell based (in India) and biochemical assays (in Norway). Binders with inhibitory activities will be subjected to crystallographic studies to understand their binding at the atomic level. The structural data will be used in a structure-guided drug design, and especially the structure-guided inhibitor design will be a very high importance aspect of the project. Developed inhibitors will be analysed by pharmacodynamics time-kill assays, toxicity and efficacy in mice models.
Our interdisciplinary team will be highly suited for the described project with expertise in synthetic biology, chemical genetics, cell biology, organic synthesis and structural biology.