Development of new strong zinc chelators and their applications in combating bacterial resistance and catalysis

Imagine a world where common infections cannot be treated with antibiotics. Resistant bacteria are rapidly becoming a major problem and are projected to cause more deaths than cancer in the not so distant future if not properly dealt with. The aim of this project was twofold. The first project would try to improve already discovered compounds that turn off one of the major defense mechanisms of bacteria, and thus render them sensitive to antibiotics. These compounds work by binding zinc, an important trace element used by bacteria to destroy antibiotics. Zinc is, however, also an important trace element and co-factor in many human enzymes so an important goal was to develop new compounds that show efficacy against resistant bacteria and at the same time are non-toxic to human cells. This part of the project ended with a compound which was highly potent and safe, both on isolated bacteria, in infected mice and in rats. The compound, ZN148, will now be out-licensed and attempted commercialized and we hope it will eventually become a drug that can save lives. The second part of the project sought to utilize the knowledge we had on zinc binding to develop new catalysts based on zinc. This project was performed at the technical university in Munich. Zinc is a co-factor in more than 6000 human enzymes and show very broad activity in the body. However, zinc catalysis has not found many applications in industry, despite the fact it has many of the wanted properties industry look for in a catalyst. It is cheap and non-toxic and it could be a safer and "greener" alternative to many toxic metals if efficient systems can be developed. This project could be characterized as a fundamental research project, and even if we synthesized more than 30 new ligands and 4 new organometallic complexes we were never able to demonstrate solid catalytic activity of the new complexes. However, we did find that some of the compounds had antimicrobial and antifungal properties which we were able to publish together with my colleagues from the University of Oslo.

One of the two primary objectives of this project was reached. We did find a compound that will reduce resistance in bacteria towards b-lactam antibiotics. This compound, ZN148 is now the lead candidate of a spin-off company which is in establishment. The second objective was not reached. We did not find new zinc-complexes that are able to catalyze carbon-carbon, carbon-nitrogen and carbon-oxygen bond formations. However, we did synthesize a number of new ligands and a handful of zinc complexes that could, in the future, be used for some of these purposes. All of the secondary objectives in the project was reached or partially reached. I did travel to the Technical University of Munich and I did learn a lot of new techniques. I most certainly did increase my personal research network with excellent researchers from Europe and we have already published one article together and we will have two more publications in 2020.

This research proposal describes the complementary and multidisciplinary activities of three institutions in Norway and two in Germany to synergistically synthesize and test new zinc-chelators as potential ligands for zinc-catalysis and as antibacterial agents to help combat multiresistant bacteria. The emergence and spread of antibiotic resistant bacteria is defined as a global threat to human health by the World Health Organization (WHO). Chief Medical Officed and advisor to the UK government, Sally Davies, ranks resistance to antibiotics as a health catastrophe in line with terrorism and climate change. This problem has also reached Norway through the dissemination of antibiotic resistant international clones. Herein, we outline a systematic and unique approach for improving a class of newly discovered inhibitors against an agressive and clinically important group of b-lactamases; namely the metallo-b-lactamases (MBLs). The inhibitors will be based on zinc chelation, which is a vital mineral for all life forms, and if done correctly, this represents a novel target. The project has a clear vision of developing lead compounds attractive for biotechnology and pharmaceutical enterprises to bring forward towards the market and thereby create additional growth in these emerging businesses. In addition, all the new zinc chelators will be tested for catalytic activity in order to search for new catalytic systems based on zinc. Zinc catalysis has not received much attention, despite the fact that zinc metalloenzymes are among the most important enzymes. We speculate that poor ligand design is the reason why zinc mediated reactions often fail to give both good yield and good (stereo)selectivity. The chelators synthesized in the MBL project will serve as excellent starting points for zinc complexes to be tested for catalytic activity. This will be done in close collaboration with TUM and will allow me to not only learn new chemistry, but also meet new collegues.