It is predicted that a failure to address the problem of antibiotic resistance will result in the death of 10 million people annually, costing the economy more than 100 trillion dollars by the year 2050. Thus, development of novel drugs based on novel molecular targets, is of the highest priority in antibiotic research. Our research proposal coincides with this need as the copper homeostasis mechanism is critical for bacterial growth and survival but was never been targeted for antimicrobial drug development before. Based on the recent structural knowledge of copper sensing protein, CueR, and its detailed mode of action we are aiming to develop corresponding inhibitors to this protein. It is important to mention that CueR homologs do not exist in human cells, therefore reducing the risk for toxic side effect as the inhibitors will be specific to microbial activity. In addition, we will utilize a unique inhibitor design called peptidomimetics, where chemical compounds mimic the 3D structure of peptides that preserve the biological functions of the peptide. Therefore, they can bind the target enzymes and inhibit their activity. The main advantages of this drug design are the high affinity of the compounds, their enhanced cell-membrane permeability, and their proteolytic resistance.

In addition, we plan to investigate the cupper homeostasis in non-pathological bacteria that are important for the marine ecosystem. For example, Gram negative microbe: Alteromonas macleodii (A. macleodii) is a ubiquitous marine bacteria found in surface waters across temperate and tropical regions. Surprisingly, the bacteria are not negatively affected by high concentration of cupper, and even successfully living and functioning in contaminated by copper water, displaying high copper tolerance. Genome and transcriptomic analyses show it possesses different CueR homologs (orthologs). By investigation of such unique phenomenon by developing of peptide/peptidomimetics probes, we plan to shield light in the general mechanisms of Gram negative microbe resistance that might be important for the medicine and sustainability related scientific questions. This project is conducting with the cooperation with Prof. Ruthstein, Bar-Ilan University.

In addition, several projects based on the peptide/peptidomimetic chemistry are undergoing in the lab: memory enhancers, TLR-4 blockers and glucose deprivation peptides for cancer treatment.